ES2210366T3 - DERIVATIVES OF AMINOTIAZOL, A MEDICINAL PRODUCT THAT CONTAINS THESE DERIVATIVES AND INTERMEDIATE PRODUCT OBTAINED DURING THE PRODUCTION OF THE COMPOUNDS. - Google Patents

Abstract

The present invention relates to an aminothiazole derivative represented by the following formula (I): <CHEM> wherein R<1>, R<2> and R<3> each independently represents a hydrogen atom, a hydroxy group, a lower alkyl group, a lower alkoxy group or the like; R<4> represents a hydrogen atom or a lower alkyl group; R<5> represents a hydrogen atom, a halogen atom or a lower alkyl group; m stands for an integer of 0 to 4, A represents a substituted amino group, a substituted imino group, a heterocyclic group or the like; and B stands for an imino group or an oxygen atom, a medicament containing it and an intermediate for the preparation of said compound. The compound has strong restoration effects on dysmotility in the gastrointestinal tract and at the same time has high safety so that it is useful as an excellent gastroprokinetic.

Description

Aminothiazole derivatives, a medicine that contains these derivatives and intermediate product obtained during The production of the compounds.

Technical field

The present invention relates to a derivative of novel aminothiazole that has enhancing effects on the dysmotility of the gastrointestinal tract, to a medication that contains the derivative and an intermediate to prepare said compound.

Background Technique

As a therapeutic agent for dismotility gastrointestinal, have been provided conventionally dopamine antagonists such as domperidone and metoclopramide, opioid agonists such as trimebutine maleate, antagonists of 5-HT 3 / agonists of 5-HT4 such as cisapride, agonists of acetylcholine such as acetylcholine chloride and the like for use clinical. In addition to these, numerous prokinetics have been studied with the purpose of treating gastrointestinal dysmotility (Japanese Patent Applications Open to Public Inspection No. HEI 1-313424, HEI 3-163074 and HEI 4-279581). These agents, however, do not they always cause sufficient effects for the improvement of dismotility There is the potential problem that possibly there are side effects due to the mechanism of action of agent even if it has sufficient effects. Therefore the agents described above are not completely satisfactory. By consequently, there is a demand for the development of a drug that have excellent dysmotility enhancing effects gastrointestinal and have fewer side effects.

Description of the invention

Given the above, the authors of the Present invention have carried out extensive research. As a result it has been discovered that an aminothiazole derivative specific has excellent dysmotility enhancing effects gastrointestinal and also has fewer side effects, leading to complete the present invention.

Therefore the present invention provides a aminothiazole derivative represented by the following formula (I):

one

where R 1, R 2 and R 3 are the same or different and each independently represents an atom of hydrogen, a hydroxy group, a lower alkyl group, a group lower alkoxy, a lower alkylcarbonyloxy group, a halogen atom, a nitro group, an amino group, a mono- group or di- (lower alkyl) amino, a mono- or di- (alkyl) group lower) carbonylamino, a formylamino group, a mono- group or di- (lower alkyl) aminoalkylamino, or R1 and R2 they can be coupled together to form a methylenedioxy group; R 4 represents a hydrogen atom or a lower alkyl group; R 5 represents a hydrogen atom, a halogen atom or a lower alkyl group; A represents a group represented by the next formula:

two

where R 6 and R 7 are the same or different and each independently represents a hydrogen atom, a lower alkyl group, a lower alkoxy group, a group hydroxy (lower alkyl), a carboxy group (alkyl lower), a group (lower alkoxy) carbonyl (alkyl lower), an alkoxy (lower) alkyl group, a group mono- or di- (lower alkyl) aminoalkyl, a group phenylalkyl which may be substituted with one or two alkoxy groups lower in the benzene ring, a heterocyclic group that contains saturated or unsaturated nitrogen that may be substituted with a lower alkyl group, or R 6 and R 7, together with the adjacent nitrogen atom, form a heterocyclic group that contains saturated or unsaturated nitrogen that may be substituted with an oxo group (O =) or 1 to 3 lower alkyl groups or hydroxy (lower alkyl), or a group represented by the next formula:

3

where R 8 and R 9 are the same or different and each independently represents an amino group, a group mono- or di- (lower alkyl) amino, a mercapto group or a (lower) alkyl group thio, or R 8 and R 9, together with the adjacent carbon atom, they form a heterocyclic group that contains nitrogen; and B represents an imino group that can be substituted with a lower alkyl group or an oxygen atom; and m represents an integer from 0 to 4; B- (CH2) m -A can form a group piperidinyl, branched alkylamino or phenylamino which may be substituted with a mono- or di- (lower alkyl) amino group, or a piperazinyl, piperidinylamino or piperidinylalkylamino group that it may be substituted with a lower alkyl group, or a salt of the same.

Also the present invention provides a medicine comprising as an effective ingredient the derivative of aminothiazole (I) described above or a salt thereof.

The present invention further provides a pharmaceutical composition comprising the derivative of aminothiazole (I) described above or a salt thereof and a carrier pharmaceutically acceptable.

The present invention further provides the use of the aminothiazole derivative (I) described above or a salt thereof as a medicine

The present invention further provides a method of prevention and treatment for diseases caused for digestive dyskinesia, which includes administering an amount Effective of the aminothiazole derivative (I) described above or a salt of Same to a patient.

The present invention further provides a thiazole derivative represented by the following general formula (II):

4

where R 1, R 2, R 3, R 4 and R 5 have the same meanings defined above, and D represents a hydroxy or lower alkoxy group or a salt thereof which is useful as an intermediate for the preparation of the compound of the invention (I).

Better ways of carrying out the invention

The term "lower" used here represents a linear, branched or cyclic carbon chain that It has 1 to 6 carbon atoms.

Therefore, among the examples of the "group lower alkyl "linear alkyl groups are included, branched or cyclic having 1 to 6 carbon atoms (which they may abbreviate hereinafter as "alkyl C 1 -C 6 ") such as methyl, ethyl, propyl, isopropyl, cyclopropyl, butyl, isobutyl, sec-butyl, t-butyl, cyclobutyl, pentyl, 1-methylbutyl, 2-methylbutyl, isopentyl, t-pentyl, 1,2-dimethylpropyl, Neopentyl, 1-ethylpropyl, cyclopentyl, hexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, isohexyl, 1-ethylbutyl, 2-ethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-methyl-1-ethylpropyl, 1-ethyl-2-methylpropyl,  1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl and cyclohexyl. Of them, I know C 1 -C 4 alkyl groups prefer linear or branched.

Among the examples of the "alkoxy group lower "linear, branched or branched alkoxy groups are included cyclics that have 1 to 6 carbon atoms (which can be abbreviate hereinafter as "alkoxy C 1 -C 6 ") such as methoxy, ethoxy, propoxy, cyclopropoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, t-butoxy, cyclobutoxy, pentyloxy, 1-methylbutoxy, 2-methylbutoxy, isopentyloxy, t-pentyloxy, 1,2-dimethylpropoxy, neopentyloxy, 1-ethylpropoxy, cyclopentyloxy, hexyloxy, 1-methylpentyloxy, 2-methylpentyloxy, 3-methylpentyloxy, isohexyloxy, 1-ethylbutoxy, 2-ethylbutoxy, 1,1-dimethylbutoxy, 1,2-dimethylbutoxy, 1,3-dimethylbutoxy, 2,2-dimethylbutoxy, 2,3-dimethylbutoxy, 3,3-dimethylbutoxy, 1-methyl-1-ethylpropoxy, 1-ethyl-2-methylpropoxy,  1,1,2-trimethylpropoxy, 1,2,2-trimethylpropoxy and cyclohexyloxy. Of them, I know prefer the linear C 1 -C 4 alkoxy groups or branched.

The term "halogen atom" used Here it represents a fluorine, chlorine, bromine or iodine atom.

The term "group (lower) alkylcarbonyl "represents a group (C 2 -C 7) alkylcarbonyl, linear, branched or cyclic, while the term "group lower alkylcarbonyloxy "represents a group (C2-C7) alkylcarbonyloxy linear, cyclic or branched. Here, they can also be given as examples of the lower alkyl portion of the group lower alkylcarbonyl or (lower) alkyl carbonyloxy exemplified above as "lower alkyl group". Among the preferred examples of the alkylcarbonyl group include acetyl groups, propionyl, butyryl and valeryl, while among the examples Preferred groups of the alkylcarbonyloxy group include groups acetyloxy, propionyloxy, butyryloxy and valeryloxy.

The term "hydroxy group (alkyl lower) "represents a hydroxyalkyl group C 1 -C 6 linear, branched or cyclic. Between Examples include hydroxymethyl groups, 1-hydroxyethyl, 2-hydroxyethyl, 1-hydroxypropyl, 2-hydroxypropyl, 3-hydroxypropyl, 1-hydroxy-2-methylethyl, 1-hydroxycyclopropyl, 2-hydroxy-cyclopropyl, 1-hydroxybutyl, 2-hydroxybutyl, 3-hydroxybutyl, 4-hydroxybutyl, 2-hydroxy-2-methylpropyl, 1-hydroxy-2,2-dimethyl ethyl, 1-hydroxy-1,2-dimethyl ethyl, 1-hydroxypentyl, 2-hydroxypentyl, 3-hydroxypentyl, 4-hydroxypentyl, 5-hydroxypentyl, 2-hydroxy-2-methylbutyl, 3-hydroxy-2-methylbutyl, 4-hydroxy-2-methylbutyl, 2-hydroxy-3-methylbutyl, 3-hydroxy-3-methylbutyl, 4-hydroxy-3-methylbutyl, 2-hydroxy-4-methylbutyl, 3-hydroxy-4-methylbutyl, 4-hydroxy-4-methylbutyl, 1-hydroxycyclopentyl, 2-hydroxycyclo-pentyl, 3-hydroxycyclopentyl, 1-hydroxyhexyl, 2-hydroxyhexyl, 3-hydroxyhexyl, 4-hydroxyhexyl, 5-hydroxyhexyl, 6-hydroxyhexyl, 2-hydroxy-2-methylpentyl, 2-hydroxy-3-methylpentyl, 2-hydroxy-4-methylpentyl, 2-hydroxy-5-methylpentyl, 3-hydroxy-2-methylpentyl, 3-hydroxy-3-methylpentyl, 3-hydroxy-4-methylpentyl, 3-hydroxy-5-methylpentyl, 4-hydroxy-2-methylpentyl, 4-hydroxy-3-methylpentyl, 4-hydroxy-4-methylpentyl, 4-hydroxy-5-methylpentyl, 5-hydroxy-2-methylpentyl, 5-hydroxy-3-methylpentyl, 5-hydroxy-4-methylpentyl, 5-hydroxy-5-methylpentyl, 1-hydroxycyclohexyl, 2-hydroxycyclohexyl, 3-hydroxycyclohexyl and 4-hydroxycyclohexyl. Of them, they are particularly preferred C 1 -C 4 hydroxyalkyl groups linear or branched.

The term "mono- or di- (alkyl group) lower) amino "represents an amino group substituted with one or two linear C 1 -C 6 alkyl groups, branched or cyclic. Examples include groups methylamino, ethylamino, propylamino, isopropylamino, cyclopropylamino, butylamino, isobutylamino, sec-butylamino, t-butylamino, cyclobutylamino, pentylamino, 1-methylbutylamino, 2-methylbutylamino, isopentylamino, t-pentylamino, 1,2-dimethylpropylamino, neopentylamino, 1-ethylpropylamino, cyclopentylamino, hexylamino, 1-methylpentylamino, 2-methylpentylamino, 3-methylpentylamino, isohexylamino, 1-ethylbutylamino, 2-ethylbutylamino, 1,1-dimethylbutylamino, 1,2-dimethylbutylamino, 1,3-dimethylbutylamino, 2,2-dimethylbutylamino, 2,3-dimethylbutylamino, 3,3-dimethylbutylamino, 1-methyl-1-ethylpropylamino, 1-ethyl-2-methylpropylamino, 1,1,2-trimethylpropylamino, 1,2,2-trimethylpropylamino, cyclohexylamino, dimethylamino, diethylamino, dipropylamino, diisopropylamino, dibutylamino, diisobutylamino, methylethylamino, methylpropylamino, methylisopropylamino, methylbutylamino, ethylpropylamino, ethylisopropylamino, ethylbutylamino, propylisopropylamino, propylbutylamino and isopropylbutylamino. Of these, the amino groups substituted each with one or two alkyl groups C_ {1} -C_ {4} linear or branched.

The group "mono- or di- (alkyl lower) carbonylamino "represents an amino group substituted with one or two groups (C 2 -C 7) alkylcarbonylamino linear, branched or cyclic. Examples include the acetylamino, propionylamino, butylamino, isobutylamino groups, cyclopropylcarbonylamino, valerylamino, isovalerylamino, sec-butylcarbonylamino, pivaroylamino, cyclobutylcarbonylamino, pentylcarbonylamino, 1-methylbutylcarbonylamino, 2-methylbutylcarbonylamino, isopentyl carbonylamino, t-pentylcarbonylamino, 1,2-dimethylpropylcarbonylamino, Neopentylcarbonylamino, 1-ethylpropylcarbonylamino, cyclopentylcarbonylamino, hexylcarbonylamino, 1-methylpentylcarbonylamino, 2-methyl-pentylcarbonylamino, 3-methylpentylcarbonylamino, isohexylcarbonylamino, 1-ethylbutylcarbonylamino, 2-ethylbutylcarbonylamino, 1,1-dimethylbutylcarbonylamino, 1,2-dimethylbutylcarbonylamino, 1,3-dimethylbutylcarbonyl amino, 2,2-dimethylbutylcarbonyl amino, 2,3-dimethylbutylcarbonylamino, 3,3-dimethylbutylcarbonylamino, 1-methyl-1-ethylpropylcarbonylamino, 1-ethyl-2-methylpropylcarbonylamino,  1,1,2-trimethylpropylcarbonylamino, 1,2,2-trimethylpropylcarbonylamino, cyclohexylcarbonylamino, diacetylamino, dipropionylamino, dibutyrylamino, diisobutyrylamino, divalerylamino, diisovalerylamino, acetylpropionylamino, acetylbutyryl amino, acetylisobutyrylamino, acetylvalerylamino, propionylbutylamino, propionylisobutyrylamino, propionylvalerylamino, butyrylisobutyrylamino, butyrylvalerylamino e isobutyrylvalerylamino. Of these, amino groups are preferred. each substituted with one or two alkyl groups C_ {2} -C_ {5} linear or branched.

Among the group examples "lower alkoxy" alkyl "groups are included alkoxy (C 1 -C 6 alkyl) such as the methoxymethyl, ethoxymethyl, propoxymethyl groups, isopropoxymethyl, butoxymethyl, isobutoxymethyl, sec-butoxymethyl, t-butoxymethyl, cyclopropoxymethyl, pentyloxymethyl, isopentyloxymethyl, hexyloxymethyl, isohexyloxymethyl, cyclopentyloxymethyl, cyclohexyloxymethyl, methoxyethyl, ethoxyethyl, propoxyethyl, isopropoxyethyl, butoxyethyl, isobutoxyethyl, sec-butoxy ethyl, t-butoxy ethyl, cyclopropoxyethyl, pentyloxyethyl, isopentyloxyethyl, hexyloxyethyl, isohexyloxyethyl, cyclopentyloxyethyl, cyclohexyloxyethyl, methoxypropyl, ethoxypropyl, propoxypropyl, isopropoxypropyl, butoxypropyl, isobutoxypropyl, sec-butoxypropyl, t-butoxypropyl, cyclopropoxypropyl, pentyloxypropyl, isopentyloxypropyl, hexyloxypropyl, isohexyloxypropyl, cyclopentyloxypropyl, cyclohexyloxypropyl, methoxybutyl, ethoxybutyl, propoxybutyl, isopropoxybutyl, butoxybutyl, isobutoxybutyl, sec-butoxybutyl, t-butoxybutyl, cyclopropoxybutyl, pentyloxybutyl, isopentyloxybutyl, hexyloxybutyl, isohexyloxybutyl, cyclopentyloxybutyl and cyclohexyloxybutyl. From they are particularly preferred groups (C 1 -C 4) alkoxy alkyl C_ {1} -C_ {4}.

Among the group examples "alkoxy- (lower) carbonylalkyl" includes groups (C 1 -C 6) alkoxycarbonylalkyl C_ {1} -C_ {6} such as groups methoxycarbonylmethyl, ethoxycarbonylmethyl, propoxycarbonylmethyl, isopropoxycarbonylmethyl, butoxycarbonylmethyl, isobutoxycarbonylmethyl, sec-butoxycarbonylmethyl, t-butoxycarbonylmethyl, cyclopropoxycarbonylmethyl, pentyloxycarbonylmethyl, isopentyloxycarbonylethyl, hexyloxycarbonylmethyl, isohexyloxycarbonylmethyl, cyclopentyloxycarbonylmethyl, cyclohexyloxycarbonylmethyl, methoxycarbonylethyl, ethoxycarbonylethyl, propoxycarbonylethyl, isopropoxycarbonylethyl, butoxycarbonylethyl, isobutoxycarbonylethyl, sec-butoxycarbonylethyl, t-butoxycarbonylethyl, cyclopropoxycarbonylethyl, pentyloxycarbonylethyl, isopentyloxycarbonylethyl, hexyloxycarbonylethyl, isohexyloxycarbonylethyl, cyclopentyloxycarbonylethyl, cyclohexyloxycarbonylethyl, methoxycarbonylpropyl, ethoxycarbonylpropyl, propoxycarbonylpropyl, isopropoxycarbonylpropyl, butoxycarbonylpropyl, isobutoxycarbonylpropyl, sec-butoxycarbonylpropyl, t-butoxycarbonylpropyl, cyclopropoxycarbonylpropyl, pentyloxycarbonylpropyl, isopentyloxycarbonylpropyl, hexyloxycarbonylpropyl, isohexyloxycarbonylpropyl, cyclopentyloxycarbonylpropyl, cyclohexyloxycarbonylpropyl, methoxycarbonylbutyl, ethoxycarbonylbutyl, propoxycarbonylbutyl, isopropoxycarbonylbutyl, butoxycarbonylbutyl, isobutoxycarbonylbutyl, sec-butoxycarbonylbutyl, t-butoxycarbonylbutyl, cyclopropoxycarbonylbutyl,  pentyloxycarbonylbutyl, isopentyloxycarbonylbutyl, hexyloxycarbonylbutyl, isohexyloxycarbonylbutyl, cyclopentyloxycarbonylbutyl and cyclohexyloxycarbonylbutyl. From they are particularly preferred groups (C 1 -C 4) alkoxycarbonylalkyl C_ {1} -C_ {4}.

Among the examples of the "carboxyalkyl group lower "carboxyalkyl groups are included C_ {1} -C_ {6}. Of them, groups are preferred C 1 -C 4 carboxyalkyl such as carboxymethyl, carboxy ethyl, carboxypropyl and carboxybutyl.

Among the examples of the "mono- or group di- (lower alkyl) aminoalkyl "groups are included mono- or di- (alkyl C 1 -C 6) aminoalkyl C_ {1} -C_ {6} such as groups methylaminomethyl, methylaminoethyl, methylaminopropyl, methylaminobutyl, ethylaminomethyl, ethylaminoethyl, ethylaminopropyl, ethylaminobutyl, propylaminomethyl, propylaminoethyl, propylaminopropyl, propylaminobutyl, isopropylaminomethyl, isopropylaminoethyl, isopropylaminopropyl, isopropylaminobutyl, butylaminomethyl, butylaminoethyl, isobutylaminomethyl, isobutylaminoethyl, sec-butylaminomethyl, t-butylaminomethyl, t-butylaminoethyl, dimethylaminomethyl, dimethylaminoethyl, dimethylaminopropyl, dimethylaminobutyl, diethylaminomethyl, diethylaminoethyl, diethylaminopropyl, dipropylaminomethyl, dipropylaminoethyl, dipropylaminopropyl, diisopropylaminomethyl, diisopropylaminoethyl, diisopropylaminopropyl, dibutylaminoethyl, dibutylaminobutyl, diisobutylaminomethyl, diisobutylaminobutyl, methylethylaminomethyl,  methylethylaminobutyl, methylpropylaminomethyl, methylpropylaminoethyl, methylpropylaminopropyl, methylpropylaminobutyl, methylisopropylaminomethyl, methylisopropylaminoethyl, methylisopropylaminopropyl, methylisopropylaminobutyl, ethylisopropylaminomethyl, ethylisopropylaminoethyl, ethylisopropylaminopropyl, ethylisopropylaminobutyl, ethylpropylaminomethyl, ethylpropylaminoethyl, ethylpropylaminopropyl, ethylpropylaminobutyl, methylbutylaminomethyl, methylbutylaminoethyl, cyclopentylisopropylaminoethyl, cyclopentylisopropylaminopropyl, cyclopentylisopropylaminobutyl, cyclopentylbutylaminomethyl, cyclopentylbutylaminoethyl, cyclopentylbutylaminopropyl, cyclopentylbutylaminobutyl, cyclohexylmethylaminomethyl, cyclohexylmethylaminoethyl, cyclohexylmethylaminopropyl, cyclohexylmethylaminobutyl, cyclohexylethylaminomethyl, cyclohexylethylaminoethyl, cyclohexylethylaminopropyl, cyclohexylethylaminobutyl, cyclohexylpropylaminomethyl, cyclohexylpropylaminoethyl, cyclohexylpropylaminopropyl, cyclohexyl isopropylaminomethyl, cyclohexyl isopropylaminoethyl, cyclohexyl isopropylaminopropyl, cyclohexyl isopropylaminobutyl, cyclohexylbutylaminomethyl, cyclohexylbutylaminoethyl, cyclohexylbutylaminopropyl and cyclohexylbutylaminobutyl. From them mono- or di- (alkyl) groups are preferred C 1 -C 4) - aminoalkyl C_ {1} -C_ {4}.

Among the examples of the group "mono- or di- (lower alkyl) aminoalkylamino "includes mono- or di- (alkyl groups C 1 -C 6) amino (alkyl C 1 -C 6) amino such as methylaminomethylamino, methylaminoethylamino, methylaminopropylamino, methylaminobutylamino, ethylaminomethylamino, ethylaminoethylamino, ethylaminopropylamino, ethylaminobutylamino, propylaminonyethylamino, propylaminoethylamino, propylaminopropylamino, propylaminobutylamino, isopropylaminomethylamino, isopropylaminoethylamino, isopropylaminopropylamino, isopropylaminobutylamino, butylaminomethylamino, butylaminoethylamino, isobutylaminomethylamino, isobutylaminoethylamino, sec-butylaminomethylamino, sec-butylaminoethylamino, t-butylaminomethylamino, t-butylaminoethylamino, dimethylaminomethylamino, dimethylaminoethylamino, dimethylaminopropylamino, dimethylaminobutylamino, diethylaminomethylamino, diethylaminoethylamino, diethylaminopropylamino, dipropylaminomethylamino, dipropylaminoethylamino, dipropylaminopropylamino, diisopropylaminomethylamino, diisopropylaminoethylamino, diisopropylaminopropylamino, dibutylaminoethylamino, dibutylaminobutylamino, diisobutylaminomethylamino, diisobutylaminobutylamino, methylethylaminomethylamino, methylethylaminobutylamino, methylpropylaminomethylamino, methylpropylaminoethylamino, methylpropylaminopropylamino, methylpropylaminobutylamino, methylisopropylaminomethylamino, methylisopropylaminoethylamino, methylisopropylaminopropylamino, methylisopropylaminobutylamino, ethylisopropylaminopropylamino, ethylisopropylaminobutylamino, ethylpropylaminomethylamino, ethylpropylaminoethylamino, ethylpropylaminopropylamino, ethylpropylaminobutylamino, methylbutylaminomethylamino, methylbutylaminoethylamino, methylbutylaminopropylamino, methylbutylaminobutylamino, ethylbutylaminomethylamino, ethylbutylaminoethylamino, ethylbutylaminopropylamino, ethylbutylaminobutylamino, propylbutylaminomethylamino, propylbutylaminoethylamino, propylbutylaminopropylamino, propylbutylaminobutylamino, isopropylbutylaminomethylamino, isopropylbutylaminoethylamino, isopropylbutylaminopropylamino, isopropylbutylaminobutylamino, dicyclopropylaminomethylamino, dicyclopropylaminoethylamino, dicyclopropylaminopropylamino, dicyclopropylaminobutylamino, methylcyclopropylaminomethylamino, methylcyclopropylaminoethylamino, methylcyclopropylaminopropylamino, methylcyclopropylaminobucylamino, ethylcyclopropylaminomethylamino, ethylcyclopropylaminoethylamino, ethylcyclopropylaminopropylamino, ethylcyclopropylaminobutylamino, cyclopropylpropylaminomethylamino, cyclopropylpropylaminoethylamino, cyclopropylpropylaminopropylamino, cyclopropylpropylaminobutylamino,  cyclopropyl isopropylaminomethylamino, cyclopropylisopropylaminoethylamino, cyclopropyl isopropylaminopropylamino, cyclopropylisopropylaminobutylamino, cyclopropylbutylaminomethylamino, cyclopropylbutylaminoethylamino, cyclopropylbutylaminopropylamino, cyclopropylbutylaminobutylamino, cyclopentylmethylaminomethylamino, cyclopentylmethylaminoethylamino, cyclopentylmethylaminopropylamino, cyclopentylmethylaminobutylamino, cyclopentylethylaminomethylamino, cyclopentylethylaminoethylamino, cyclopentylethylaminopropylamino, cyclopentylethylaminobutylamino, cyclopentylpropylaminomethylamino, cyclopentylpropylaminoethylamino, cyclopentylpropylaminopropylamino, cyclopentylisopropylaminomethylamino, cyclopentylisopropylaminoethylamino, cyclopentylisopropylaminopropylamino, cyclopentylisopropylaminobutylamino, cyclopentylbutylaminomethylamino, cyclopentylbutylaminoethylamino, cyclopentylbutylaminopropylamino, cyclopentylbutylaminobutylamino, cyclohexylmethylaminoethylamino, cyclohexylmethylaminoethylamino, cyclohexylmethylaminopropylamino, cyclohexylmethylaminobutylamino, cyclohexylethylaminomethylamino, cyclohexylethylaminoethylamino, cyclohexylethylaminopropylamino, cyclohexylethylaminobutylamino, cyclohexylpropylaminonethylamino, cyclohexylpropylaminoethylamino, cyclohexylpropylaminopropylamino, cyclohexyl isopropylaminomethylamino, cyclohexyl isopropylaminoethylamino, cyclohexyl isopropylaminopropylamino, cyclohexyl isopropylaminobutylamino, cyclohexylbutylaminomethylamino, cyclohexylbutylaminoethylamino, cyclohexylbutylaminopropylamino and cyclohexylbutylaminobutylamino. Of them are particularly preferred mono- or di- (alkyl groups) C 1 -C 4) amino (C 1 -C 4 alkyl) amino.

Among the examples of the "phenylalkyl" group groups such as benzyl, phenethyl, groups are included 1-phenylethyl, 1-phenylpropyl, 2-phenylpropyl, 3-phenylpropyl, 1-methyl-1-phenylethyl, 1-ethyl-2-phenylethyl, l-phenylbutyl, 2-phenylbutyl, 3-phenylbutyl, 4-phenylbutyl, 1-benzylpropyl, 1-methyl-1-phenylpropyl, 1-methyl-2-phenylpropyl, l-methyl-3-phenylpropyl, 2-methyl-1-phenylpropyl, 2-methyl-2-phenylpropyl, 2-methyl-3-phenylpropyl Y 1,1-dimethyl-2-phenylethyl.

Among the examples of the "group alkyl (lower) uncle "groups are included (C 1 -C 6) alkyl thio such as the methylthio, ethylthio, propylthio, isopropylthio groups, cyclopropylthio, butylthio, isobutylthio, sec-butylthio, t-butylthio, cyclobutylthio, pentylthio, 1-methylbutylthio, 2-methylbutylthio, isopentylthio, t-pentylthio, 1,2-dimethylpropylthio, neopentylthio, 1-ethylpropylthio, cyclopentylthio, hexylthio, 1-methylpentylthio, 2-methylpentylthio, 3-methylpentylthio, isohexylthio, 1-ethylbutylthio, 2-ethylbutylthio, 1,1-dimethylbutylthio, 1,2-dimethylbutylthio, 1,3-dimethylbutylthio, 2,2-dimethyl-butylthio, 2,3-dimethylbutylthio, 3,3-dimethylbutylthio, 1-methyl-1-ethylpropylthio, 1-ethyl-2-methylpropylthio, 1,1,2-trimethylpropylthio, 1,2,2-trimethylpropylthio and cyclohexylthio. From them, groups are particularly preferred (C 1 -C 4) alkyl uncle.

The term "heterocyclic group containing saturated nitrogen "represents a heterocyclic group of 5-7 saturated members containing at least one atom of nitrogen in its ring. Among the preferred examples 5-6 heterocyclic groups are included saturated members each containing one or two atoms of nitrogen and 0 or 1 oxygen or sulfur atom, such as groups pyrrolidinyl, imidazolidinyl, pyrazzalidinyl, oxazalidinyl, thiazolidinyl, isoxazalidinyl, isothiazolidinyl, piperidinyl, piperazinyl, morpholino and thiomorpholino.

The "nitrogen-containing heterocyclic group unsaturated "represents a heterocyclic group of 5-7 unsaturated members containing at least one nitrogen atom in the ring thereof. Groups are preferred heterocyclic 5-6 unsaturated members that each contain 1 to 4 nitrogen atoms and 0 or 1 atoms of oxygen or sulfur Specific examples include the pyrrolyl, imidazolyl, pyrazolyl, triazolyl, oxazolyl groups, thiazolyl, isooxazolyl, isothiazolyl, pyridyl, dihydropyridyl and tetrahydropyridyl.

Among the examples of the "alkylamino group branched "groups are included (C 2 -C 6) alkyl amino branched, more specifically, isopropylamino groups, sec-butylamino and isobutylamino.

Among the group examples "piperidinylalkylamino" groups are included piperidinyl (alkyl C 1 -C 6) amino, more specifically, the piperidinylmethylamino and piperidinylethylamino groups.

In the compound (I) of the invention, it is preferred that one of R 1, R 2 and R 3 represents an alkoxy group lower, nitro or formylamino and the other two are selected from a hydrogen atom, a hydroxy group, a lower alkyl group, a lower alkoxy group, a group lower alkylcarbonyloxy, a halogen atom, a nitro group, an amino group, a mono- or di- (alkyl group lower) amino, a mono- or di- (alkyl) group lower) carbonylamino, a formylamino group and a mono- group or di- (lower alkyl) aminoalkyl. As for the group nitrogen-containing heterocyclic independently represented for R 6 and R 7, groups are particularly preferred piperidinyl, piperazinyl and pyridyl.

As for the heterocyclic group it contains nitrogen that is formed by R 6 and R 7 together with the atom of adjacent nitrogen, heterocyclic groups are preferred which they contain saturated nitrogen, particularly preferred being pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl groups, piperazinyl, isoxazolidinyl and morpholino.

As for the saturated heterocyclic group that contains nitrogen that is formed by R 8 and R 9 together with the adjacent carbon atom, particularly preferred are pyrrolidinyl, imidazolidinyl, pyrazolidinyl groups, oxazolidinyl, thiazolidinyl.

In formula (I), it is preferred that one of R 1, R 2 and R 3 represent a lower alkoxy group, nitro or formylamino and the other two are selected from an atom of hydrogen, a hydroxy group, a lower alkyl group, a group lower alkoxy, a group (lower) alkylcarbonyloxy, an atom of halogen, a nitro group, an amino group, a mono- or group di (lower alkyl) amino, a mono or di- (alkyl) group lower) carbonylamino, a formylamino group and a group mono- or di- (lower alkyl) aminoalkylamino; R 4 represents a hydrogen atom or a lower alkyl group; R 5 represents a hydrogen atom, a halogen atom or a lower alkyl group; A represents -N (R 6) R 7 (where R 6 and R 7 have the same meanings defined above); B represents a group imino which may be substituted with a lower alkyl group; and m Represents 2 to 4.

In addition, in formula (I), it is particularly preferred that one of R 1, R 2 and R 3 represents a group lower alkoxy, nitro or formylamino and the other two are selected between a hydrogen atom, a hydroxy group, an alkoxy group lower and a halogen atom; B represents an imino group that it may be substituted with a lower alkyl group; m represents from 2 to 4; and A represents -N (R 6) R 7 (where R 6 and R 7 have the same defined meanings before).

The compound (I) of the invention or intermediate (II) for the preparation of the compound of the invention can be converted into its salt in a manner known per se in the art. Examples of the salt of the compound (I) of the invention or intermediate (II) include acid addition salts with an inorganic acid, such as hydrochloride, sulfate, nitrate, phosphate, hydrobromide and hydroiodide; and acid addition salts with an organic acid such as acetate, oxalate, malonate, succinate, maleate, fumarate, lactate, malate, citrate, tartrate, methanesulfonate and ethanesulfonate.

The present invention also encompasses various solvates, such as hydrates, of the compound (I) of the invention or the intermediate (II).

The compound (I) of the invention manifests proton tautomería times, specifically tautomería imine-enamine. Among the examples of such Tautomería include:

5

The compound (I) of the invention or the intermediate (II) can be prepared by various procedures of synthesis, taking into account its basic skeleton or the characteristics of your group The typical synthesis procedures (A and B) for this will be described below. Here it is possible preparing the compound of the invention by any one of the preparation procedures A and B and procedures in accordance with they.

Preparation Procedure TO

6

where X represents a removable group such as a p-nitrophenoxy group, a halogen atom or a hydroxy group, and R 1, R 2, R 3, R 4, R 5, A, B, D and m have the same defined meanings before.

This procedure will be described later. through each stage.

Stage A1

A thiazole derivative (II) can be prepared by reacting the compound represented by the formula (III) with the compound represented by the formula (IV). The reaction is carried out in the presence or absence of a base, for example a alkali metal carbonate such as potassium carbonate, potassium bicarbonate, sodium carbonate or sodium bicarbonate, an alkali metal hydroxide such as potassium hydroxide, sodium hydroxide or lithium hydroxide, an alkylamine such as triethylamine or diisopropylethylamine, or a compound with a base of pyridine such as pyridine, lutidine or 4-dimethylaminopyridine without solvent or in a solvent that does not influence the reaction, for example an aprotic polar solvent such as acetonitrile, N, N-dimethylformamide or dimethylsulfoxide, a solvent with a halogenated base such as methylene chloride, chloroform or 1,2-dichloroethane, a solvent with a ether base such as ether, tetrahydrofuran or dioxane or a solvent with a benzene base such as toluene. The reaction is It can be carried out at room temperature or by heating.

When the X of Compound (III) represents a hydroxy group, the main reaction can be carried out once it has become a highly reactive substituent such as a p-nitrophenoxy group or a halogen atom in a manner known per se I know in the art.

Incidentally, when a derivative of thiazole (II) or a compound (I) of the invention containing as any of R 1, R 2 and R 3 an amino group or a group amino substituted with lower alkyl, the main reaction is effect after protection of the amino group of Compound (III), followed by deprotection after the main reaction or after subsequent step A2 reaction; or the main reaction is effect using a compound (III) containing nitro, followed by reduction after the main reaction or after the stage reaction A2 to convert the nitro group into an amino group.

When a thiazole (II) derivative or a compound (I) of the invention containing a hydroxy group as Any of R 1, R 2 and R 3, the Compound (III) containing an alkoxy group instead of which It contains a hydroxy group. In this case, after the main reaction or the reaction of the subsequent step A2, the alkoxy group is converts into a hydroxy group by means of a reaction of dealkylation using a pyridine hydrochloride, tribromide boron, a solution of hydrogen bromide solution in acid acetic, a catalytic reduction or similar.

When a thiazole (II) derivative or a compound (I) of the invention containing a group lower alkylcarbonyloxy as any of R 1, R 2 and R 3, a carboxylic acid or a reactive derivative thereof with the compound of the invention that is has prepared before and contains a hydroxy group like any of R 1, R 2 and R 3.

When a thiazole (II) derivative or a compound (I) of the invention containing as any of R 1, R 2 and R 3 a halogen atom, a hydroxy group or a nitro group, a nitrite salt and a strong acid are actuated on the compound (III) containing amino to convert it into a diazonium salt and then the resulting diazonium salt becomes in various substituents by a substitution reaction (Sandmeyer's method, Gattermann reaction, reaction of Schiemann). This operation can be carried out after the main reaction or after the reaction of step A2 subsequent.

Stage A2

The compound (I) of the invention can be obtained by reacting the thiazole derivative (II) obtained in the step A1 with Compound (V) and then subjecting the reaction mixture to an N-substitution reaction as required. The reaction is carried out as in Stage A1.

When the D of the thiazole derivative (II) represents a hydroxy group, it is also possible to carry out the main reaction after converting the derivative into a highly reactive substituent such as a p-nitrophenoxy group or a halogen atom in a manner known per se I know in the art.

The compound (I) of the invention can be introduced into another compound (I) of the invention by subjecting it to a N-substitution reaction or a reaction of O-replacement The reaction of N-replacement can be done by a method known to date such as monoalkylation, dialkylation or amidation More specifically, the N-substitution is can be carried out as needed by a reaction in the which are used in combination a reducing agent such as acid formic or borohydride and an aldehyde such as formaldehyde, acetaldehyde or glyoxal or an acid anhydride such as anhydride acetic acid, a reaction in which a carboxylic acid or a reactive derivative thereof, a reaction in which a alkyl halide, a reaction in which a compound is used which contains a removable group such as a lower alkoxy group, (lower) alkyl uncle, (lower) alkyl sulfonyl or (lower) alkyl sulfinyl, or a halogen atom, a reduction reaction in which an aldehyde or ketone is actuated to form an imine derivative, followed by the addition of a compound of borohydride or a hydrogenation reaction in which it is used palladium-carbon or similar as catalyst, or a combination thereof. By the way, when a halide of alkyl substituted with phthalimide in the reaction of N-substitution using an alkyl halide, is possible to convert the phthalimido group to an amino group by a base such as methylamine (Gabriel's synthesis) and then submit the resulting amino group to a reaction of N-replacement

The O-substitution reaction is You can perform using the method known to date such as alkylation or acylation. It is possible to carry out the reaction of O-replacement as needed according to the reaction in which a carboxylic acid or a derivative is used reagent thereof or the reaction in which a halide of alkyl, or a combination thereof.

By the way, as for Compound (V), you can employ a compound commercially or alternatively available, This can be prepared using the reactions described above. for N-substitution combined as need.

Procedure B

7

where X, R 1, R 2, R 3, R 4, R 5, A, B, D and m have the same defined meanings before.

Stage B1

Compound (VI) can be prepared by making react Compound (IV) with Compound (V). The reaction is performed in a manner similar to Stage A2.

Stage B2

Compound (VI) obtained in Step B1 can be introduced into the compound (I) of the invention making it react with Compound (III). The reaction is carried out in one similar to Stage A1.

By the way, when compound (I) of the invention containing as any of R 1, R 2 and R 3 an amino group or an alkyl substituted amino group lower, the main reaction is carried out after the protection of the amino group of Compound (III), followed by deprotection; wave main reaction is carried out using a compound (III) that contains nitrogen, followed by reduction after the main reaction or after the reaction of Step A2 to convert the nitro group into an amino group

When a thiazole derivative (II) or a compound (I) of the invention is prepared which contains as any of R 1, R 2 and R 3 a hydroxy group, it is possible to use a Compound (III) containing alkoxy instead of using a Compound (III) containing hydroxy. When the Alkoxy-containing Compound (III) is used, the derivative or compound of the invention is prepared, after the main reaction or the reaction of Step A2, by a dealkylation reaction using pyridine hydrochloride, boron tribromide, a solution of hydrogen bromide solution in acetic acid, or a catalytic reduction to convert the alkoxy group into a group
hydroxy

When the thiazole derivative (II) or the compound (I) of the invention containing as any of R 1, R 2 and R 3 an alkylcarbonyloxy group, is made act a carboxylic acid or a derivative reactive with the compound of the invention that has been prepared before and contains as any of R 1, R 2 and R 3 a hydroxy group.

When the thiazole derivative (II) or the compound (I) of the invention containing as any of R 1, R 2 and R 3 a halogen atom, a hydroxy group or a nitro group, a nitrite salt and a strong acid are actuated on the compound (III) containing amino to convert it into a diazonium salt and then the resulting diazonium salt becomes in various substituents by the substitution reaction (Sandmeyer's method, Gattermann reaction, Shiemann reaction). This procedure can be carried out after the main reaction or after the subsequent step A2 reaction.

Compound (I) of the invention prepared by any of the Preparation Procedures A and B described above and the processes according to them can be prepared in the form of a salt in a manner known per se in the art.

Compound (I) of the invention thus obtained it has, as will be described later, excellent effects gastrointestinal dysmotility enhancers and at the same time It has high safety so it is useful for prevention and the treatment of dysmotility of the gastrointestinal tract. Among the examples of symptoms and diseases caused by digestive dysmotility includes epigastric discomfort, nausea, vomiting, heartburn, anorexia, epigastric pain, abdominal flatulence, chronic gastritis, esophagitis of reflux and post-gastrectomy syndrome.

The compound (I) of the invention can be formed as a composition for oral administration or parenteral, mixed with a pharmaceutically acceptable carrier. The compound (I) of the invention can be formulated in tablets, powders, granules or capsules adding suitable additives, by example, an excipient such as lactose, mannitol, corn starch or crystalline cellulose, a binder such as a derivative of cellulose, gum arabic or gelatin, a disintegrant such as salt carboxymethyl cellulose calcium and a lubricant such as talc or magnesium stearate as needed. These solid preparations they can also be formed in a coated preparation enteric using a coverage base such as phthalate from hydroxypropyl methylcellulose acetate acetate succinate hydroxypropyl methylcellulose, cellulose acetate phthalate or copolymer methacrylate As for the composition for administration parenterally, the compound of the invention can be formulated in a liquid agent for injections using water, ethanol glycerin and commonly used surfactants, or in a suppository using a combined suppository base.

The dosage of the compound (I) of the invention varies depending on age, weight, symptoms, effects of treatment, method of administration and duration of administration. In the case of oral administration, the compound (I) is usually administered at a dose of 0.1 to 2,000 mg / day, preferably 1 to 300 mg / day in one to three servings at day.

Gastroprokinetic activity

Transducers of chronically implanted force (F-121S; Star Medical) on the antrum gastric and duodenum of a male dog (weight: 9 to 10 kg) [Itoh, Z. et al., Am. J. Dig. Dis., 22, 117-124 (1,977)]. The test was carried out two hours after feeding (30 g / kg, Gaines food; Ajinomoto General Foods). Signs of contraction obtained from each transducer were amplified (RTA-1200; Nihon Kohden) and registered in a Recorder and a computer.

The area under the contraction wave and the line Antrum base was integrated through an analysis program (DSSFFT, V. 21; Nihon Kohden). The motor activity of the club was expressed as the motor index. The test compound was dissolved in physiological saline solution and administered intravenously.

The results were calculated using the following equation and are shown in Table 1 as the% of the index motor.

\ text {(%) of the Index engine} = \ frac {\ text {Engine index for 10 minutes after administration}} {\ text {Engine index for 10 minutes before administration}} x 100

TABLE 1

Compound Dose (mg / kg) Motor index (%) Compound of Ex. 3 5 202.3 Compound of Ex. 6 5 284.5 Compound from Ex. 9 5 316.7 Compound of Ex. 10 one 254.8 Compound of Ex. eleven one 310.7 Compound from Ex. 12 0.5 229.5 Compound of Ex. 17 5 356.0 Compound of Ex. 18 5 299.0 Compound from Ex. 19 5 420.9 Compound of Ex. 21 one 157.1 Compound of Ex. 38 one 213.3 Compound from Ex. 115 one 342.9 Compound of Ex. 117 one 437.4 Compound of Ex. 156 one 257.0 Compound from Ex. 162 one 265.7

Toxicity Test

Three ICR mice were used (4-5 weeks) in each group. Test compound suspended with 5% gum arabic was supplied orally to a 500 mg / kg dose. In one week of observation, it was not observed No case of death in any group.

Examples

The present invention will be described hereinafter more specifically by Reference Examples and Examples but however, it should be considered that the present invention is not limited to or by the following examples.

Reference Example one

2- [N- (3,4-Dimethoxybenzoyl) amino] -4- (ethoxycarbonyl) -1,3-thiazole

21.3 g of were suspended 2-amino-4-ethoxycarbonyl-1,3-thiazole in 100 ml of methylene chloride, followed by the addition of 24.8 g of 3,4-dimethoxybenzoyl chloride, 25.3 g of triethylamine and 0.15 g of 4-dimethylamino-pyridine. Mix The resulting was refluxed for 2 hours. Once the reaction mixture was allowed to cool, separated by distillation methylene chloride under reduced pressure. To the residue, 1,000 ml of water was added. The precipitated crystals of this mode were collected by filtration and then recrystallized from ethanol, whereby 30.3 g of the title compound were obtained. Yield: 73%.

1 H NMR (CDCl 3) δ: 1.93 (3H, t), 3.95 (3H, s), 3.97 (3H, s), 4.39 (2H, c), 6.95 (1H, d), 7.46-7.51 (2H, m), 7.88 (1H, s), 9.91 (1H, wide s).

Reference Example two

2- [N- (2,4,5-Trimethoxybenzoyl) amino] -4- (ethoxycarbonyl) -1,3-thiazole

In a manner similar to Reference Example 1, except that chloride was used 2,4,5-trimethoxybenzoyl instead of 3,4-dimethoxybenzoyl, the compound of the Title.

IR (KBr) cm -1: 3299, 3127, 1728, 1665

1 H NMR (CDCl 3) δ: 1.42 (3H, t), 3.92 (3H, s), 3.97 (3H, s), 4.09 (3H, s), 4.43 (2H, c), 6.58 (1H, s), 7.77 (1H, s), 7.85 (1H, s), 11.13 (1H, s width).

Reference Example 3

2- [N- (3,4,5-Trimethoxybenzoyl) amino] -4- (hydroxycarbonyl) -1,3-thiazole

15 g of were suspended 2- [N- (2,4,5-trimethoxybenzoyl) amino] -4- (ethoxycarbonyl) -1,3-thiazole obtained in Reference Example 2 in 100 ml of methanol, followed of the addition of an aqueous solution that had been obtained dissolving 8.19 g of sodium hydroxide in 100 ml of water. The resulting mixture was stirred at room temperature for a time. The reaction mixture became acidic with 1N hydrochloric acid. and crystals precipitated in this way were collected by filtration, whereby 9.2 g of the title compound were obtained. Yield: 66%.

MS (FAB, m / z): 399 (MH +)

IR (KBr) cm -1: 1719, 1655

1 H NMR (DMSO-d_6) δ: 3.78 (3H, s), 3.92 (3H, s), 4.03 (3H, s), 6.85 (1H, s), 7.43 (1H, s), 8.00 (1H, s), 9.00 (1H, s width), 11.52 (1H, width s).

Reference Example 4

2- [N-Methyl-N- (3,4-dimethoxybenzoyl) amino] -4- (ethoxycarbonyl) -1,3-thiazole

In a manner similar to Reference Example 1, except that it was used 2- (N-methylamino) -4- (ethoxycarbonyl) -1,3-thiazole instead of 2-amino-4-ethoxycarbonyl-1,3-thiazole, the title compound was obtained.

MS (EI, m / z): 350 (M +)

IR (KBr) cm -1: 1719, 1655

1 H NMR (DMSO-d6) δ: 1.41 (3H, t), 3.80 (3H, s), 3.92 (3H, s), 3.95 (3H, s), 4.41 (2H, c), 6.93-6.96 (1H, m), 7.15-7.21 (2H, m), 7.90 (1H, s).

Reference Example 5

2- (N-Methylamino) -4 - [(2-dimethylaminoethyl) aminocarbonyl] -1,3-thiazole

2.5 g of dissolved 2- (N-methylamino) -4- (ethoxycarbonyl) -1,3-thiazole in 3.5 g of N, N-dimethylethylene diamine, followed stirring at 100 ° C for 6 hours. The reaction mixture is poured into isopropyl alcohol and the precipitated crystals of this mode were collected by filtration, whereby 1.68 g were obtained of the title compound. Yield: 51.5%.

MS (EI, m / z): 228 (M +)

IR (KBr) cm -1: 3395, 3198, 3104, 2824, 1657

1 H NMR (CDCl 3) δ: 2.27 (6H, s), 2.50 (2H, t), 2.97 (3H, d), 3.49 (2H, m), 5.37 (1H, wide), 7.30 (1H, s), 7.46 (1H, wide).

Reference Example 6

Acetate 2- [N- (4,5-dimethoxy-2-hydroxybenzoyl) amino] -4- (ethoxycarbonyl) -1,3-thiazole

At 18.2 g of 2- [N- (2,4,5-trimethoxybenzoyl) amino] -4- (ethoxycarbonyl) -1,3-thiazole  obtained in Reference Example 2, 17.5 g of pyridine chloride, 3.93 g of pyridine and 150 ml of N, N-dimethylformamide, followed by reflux for 6 hours. The reaction mixture was poured into ice water. The crystals precipitated in this way were collected by filtration, washed with water and then dried under reduced pressure. The crystals thus obtained were recrystallized from acid acetic, whereby 14.3 g of the title compound were obtained. Yield: 70%.

MS (EI, m / z): 413 (M +)

IR (KBr) cm -1: 3135, 1715, 1709, 1644

1 H NMR (DMSO-d6) δ: 1.31 (3H, t), 1.91 (3H, s), 3.78 (3H, s), 3.83 (3H, s), 4.30 (2H, c), 6.61 (1H, s), 7.64 (1H, s), 8.11 (1H, s), 11.5 (1H, wide s), 12.4 (1H, wide s).

Example 1 Maleate 2- [N-methyl- (3,4-dimethoxybenzoyl) amino] -4 - [(2-dimethylaminoethyl) aminocarbonyl] -1,3-thiazole

Preparation Procedure TO

A mixture of 8.41 g of 2- [N-methyl-N- (3,4-dimethoxybenzoyl) amino] -4- (ethoxycarbonyl) -1,3-thiazole obtained in Reference Example 4 and N, N-dimethyl ethylenediamine was stirred at 100 ° C for 4 hours. Having allowed it to cool, the reaction mixture was purified by column chromatography of silica gel (chloroform: methanol = 5: 1), whereby they were obtained 7.8 g of the title compound as a free base. The compound obtained in this way became your maleate and so, it He obtained the title compound. Yield: 82%.

MS (EI, m / z): 392 (M +)

IR (KBr) cm -1: 3380, 1649

1 H NMR (DMSO-d_ {6}) δ: 2.84 (6H, s), 3.21-3.35 (2H, m), 3.60-3.66 (2H, m), 3.70 (3H, s), 3.82 (3H, s), 3.84 (3H, s), 6.01 (2H, s), 7.09 (1H, d), 7.25-7.28 (2H, m), 7.93 (1H, s), 8.56 (1H, t), 8.60-10.00 (1H, width), 13.00-14.00 (1H, width).

Preparation Procedure B

1.68 g of were stirred 2- (N-Methylamino) -4 - [(2-dimethylaminoethyl) aminocarbonyl] -1,3-thiazole obtained in Reference Example 5 and 2.23 g of 3,4-dimethoxyphenyl benzoate p-nitrophenyl at 140 ° C for 6 hours. The mixture of reaction was dissolved in chloroform, washed successively with a saturated aqueous sodium bicarbonate and saline solution saturated and then dried. The solvent was distilled off and the residue was recrystallized from ethyl acetate, whereby obtained 675 mg of the title compound as a base free. The compound obtained in this way became a maleate as in Preparation Procedure 1 and thus, the title compound.

Example 2 Hydrochloride 2- [N- (3,4-dimethoxybenzoyl) amino] -4 - [(2-aminoethyl) aminocarbonyl] -1,3-thiazole

A mixture of 8 g of 2- [N- (3,4-dimethoxybenzoyl) amino] -4- (ethoxycarbonyl) -1,3-thiazole obtained in Reference Example 1 and 14.3 g of ethylenediamine are stirred at 100 ° C for one hour. The reaction mixture was subjected to distillation under reduced pressure. To the residue, 50 ml of methanol and crystals thus precipitated were collected by filtration, whereby 6.5 g of the title compound were obtained in the form of a free base. The compound became his hydrochloride and thus, the title compound was obtained. Yield: 78%.

MS (FAB, m / z): 351 (MH +)

IR (KBr) cm -1: 3400, 3381, 1653, 1650

1 H NMR (DMSO-d_ {6}) δ: 2.99 (2H, m), 3.56 (2H, m), 3.86 (3H, s), 3.87 (3H, s), 7.11 (1H, d), 7.73-7.80 (2H, m), 8.14 (3H, wide), 8.23 (1H, t), 12.68 (1H, wide), 13.00-14.00 (1H, width).

In a manner similar to Example 1 or 2, prepared the compounds of Examples 3 to 21 that will be described below using a compound selected from those obtained in Reference Examples 1 to 5.

Example 3 Maleate 2- [N- (3,4-Dimethoxybenzoyl) amino] -4 - [(2-dimethylaminoethyl) aminocarbonyl] -1,3-thiazole

MS (FAB, m / z): 379 (MH +)

IR (KBr) cm -1: 3359, 1650, 1551

1 H NMR (DMSO-d_ {6}) δ: 2.83 (6H, s), 3.24 (2H, t), 3.64 (2H, c), 3.86 (3H, s), 3.87 (3H, s), 6.03 (2H, s), 7.12 (1H, d), 7.71-7.80 (2H, m), 7.88 (1H, s), 8.20 (1H, s width), 12.58 (3H, width s).

Example 4 Dihydrochloride 2- [N- (3,4-dimethoxybenzoyl) amino] -4 - [[2- (1-imidazolyl) ethyl] aminocarbonyl] -1,3-thiazole

MS (EI, m / z): 401 (M +)

IR (KBr) cm -1: 3142, 1676, 1578

1 H NMR (DMSO-d_ {6}) δ: 3.73-3.86 (8H, m), 4.39-4.42 (2H, m), 7.11 (1H, d), 7.66-8.28 (6H, m), 9.20-9.21 (1H, m), 12.64 (1H, wide), 14.77 (1H, wide), 13.00-14.00 (1H, width).

Example 5 2- [N- (3,4-Dimethoxybenzoyl) amino] -4 - [(2-diethylaminoethyl) aminocarbonyl] -1,3-thiazole

MS (FAB, m / z): 407 (MH +)

IR (KBr) cm -1: 3390, 3246, 1684, 1659

1 H NMR (DMSO-d_ {6}) δ: 1.25 (6H, t), 3.13-3.25 (6H, m), 3.65-3.72 (2H, m), 3.87 (6H, s), 7.12 (1H, d), 7.73-7.80 (2H, m), 7.96 (1H, s), 8.40 (1H, t), 10.57 (1H, wide), 12.67 (1H, width).

Example 6 Maleate 2- [N- (3,4-dimethoxybenzoyl) amino] -4 - [(2-diisopropylaminoethyl) aminocarbonyl] -1,3-thiazole

MS (EI, m / z): 434 (M +)

IR (KBr) cm -1: 3403, 1671, 1651.

1 H NMR (DMSO-d_ {6}) δ: 1.30 (12H, d), 3.10-3.78 (6H, m), 3.86 (6H, s), 6.05 (2H, s), 7.12 (1H, d), 7.70-7.89 (3H, m), 3.80-3.70 (3H, width), 12.54 (1H, s).

Example 7 Fumarate of 2- [N- (3,4-dimethoxybenzoyl) amino] -4- [N-methyl-N- (2-dimethylaminoethyl) aminocarbonyl] -1,3-thiazole

MS (FAB, m / z): 393 (MH +)

IR (KBr) cm -1: 3453, 1617, 1516, 1269.

1 H NMR (DMSO-d_ {6}) δ: 2.40 (6H, width), 2.81 (2H, m), 3.06 (3H, m), 3.68 (2H, wide s), 3.85 (3H, s), 6.59 (2H, s), 7.11 (1H, d), 7.59 (1H, d), 7.77 (2H, m).

Example 8 Maleate 2- [N- (2,4-dimethoxybenzoyl) amino] -4 - [(2-dimethylaminoethyl) aminocarbonyl] -1,3-thiazole

MS (EI, m / z): 377 (M +)

IR (KBr) cm -1: 3335, 1709, 1653.

1 H NMR (DMSO-d_ {6}) δ: 2.59 (2H, t), 2.84 (6H, s), 3.61 (2H, c), 3.89 (3H, s), 4.04 (3H, s), 6.02 (2H, s), 6.73-6.80 (2H, m), 7.87-7.96 (2H, m), 8.47 (1H, t), 8.60-10.00 (1H, width), 11.23 (1H, s), 13.00-14.00 (1H, width).

Example 9 Maleate 2- [N- (2,4,5-Trimethoxybenzoyl) amino] -4 - [(2-dimethylaminoethyl) aminocarbonyl] -1,3-thiazole

MS (EI, m / z): 407 (M +)

IR (KBr) cm -1: 3322, 1657, 1611.

1 H NMR (DMSO-d_ {6}) δ: 2.83 (6H, s), 3.25 (2H, t), 3.60 (2H, t), 3.78 (3H, s), 3.93 (3H, s), 4.07 (3H, s), 6.02 (2H, s), 6.89 (1H, s), 7.51 (1H, s), 7.89 (1H, s), 8.52 (1H, t), 8.60-10.00 (1H, width), 11.25 (1H, s), 13.00-14.00 (1H, width).

Example 10 Maleate 2- [N- (2,4,5-Trimethoxybenzoyl) amino] -4 - [(2-diethylaminoethyl) aminocarbonyl] -1,3-thiazole

MS (FAB, m / z): 437 (MH +)

IR (KBr) cm -1: 3380, 3331, 1664, 1610

1 H NMR (DMSO-d_ {6}) δ: 1.21 (6H, t), 3.16-3.26 (6H, m), 3.57-3.64 (2H, m), 3.93 (3H, s), 4.07 (3H, s), 4.20 (3H, s), 6.01 (2H, s), 6.89 (1H, s), 7.51 (1H, s), 7.89 (1H, s), 8.51 (1H, width), 11.24 (1H, width), 13.00-14.00 (1H, width).

Example 11 Maleate 2- [N- (2,4,5-Trimethoxybenzoyl) amino] -4 - [(2-diisopropylaminoethyl) aminocarbonyl] -1,3-thiazole

MS (EI, m / z): 464 (M +)

IR (KBr) cm -1: 3320, 1660, 1609

1 H NMR (DMSO-d_ {6}) δ: 1.29 (12H, d), 3.18-3.77 (6H, m), 3.79 (3H, s), 3.93 (3H, s), 4.07 (3H, s), 6.02 (2H, s), 6.89 (1H, s), 7.51 (1H, s), 7.89 (1H, s), 8.50-8.55 (2H, width), 13.00-14.00 (1H, width).

Example 12 Maleate 2- [N- (2,4,5-Trimethoxybenzoyl) amino] -4- [N-methyl-N- (2-diisopropylaminoethyl) aminocarbonyl] -1,3-thiazole

MS (EI, m / z): 478 (M +)

IR (KBr) cm -1: 3333, 1657, 1620

1 H NMR (DMSO-d_ {6}) δ: 1.15-1.43 (12H, width), 3.02-3.78 (12H, m), 3.92 (3H, s), 4.04 (3H, s), 6.03 (2H, s), 6.87 (1H, s), 7.46 (1H, width), 7.70 (1H, s), 8.30-8.90 (1H, width), 11.30-11.45 (1H, m), 13.00-14.00 (1H, width).

Example 13 2- [N- (2,4,5-Trimethoxybenzoyl) amino] -4 - [[2- (N-isopropyl-N-methylamino) ethyl] aminocarbonyl] -1,3- thiazole

MS (FAB, m / z): 437 (MH +)

IR (KBr) cm -1: 3320, 2965, 1657

1 H NMR (CDCl 3) δ: 1.05 (6H, d), 2.27 (3H, s), 2.62 (2H, t), 2.90 (1H, m), 3.49 (2H, dd), 3.93 (3H, s), 3.99 (3H, s), 4.11 (3H, s), 6.59 (1H, s), 7.64 (1H, wide s), 7.74 (1H, s), 7.78 (1H, s), 11.05 (1H, s).

Example 14 Dihydrochloride 2- [N- (2,4,5-trimethoxybenzoyl) amino] -4 - [[2- (N-isopropyl-N-ethylamino) ethyl] aminocarbonyl] -1,3-thiazole

MS (EI, m / z): 451 (MH +)

IR (KBr) cm -1: 3350, 2970, 1655, 1609

1 H NMR (DMSO-d6) δ: 1.27 (9H, m), 3.16 (4H, m), 3.64 (3H, wide s), 3.78 (3H, s), 3.93 (3H, s), 4.08 (3H, s), 6.89 (1H, s), 7.51 (1H, s), 7.90 (1H, s), 8.69 (1H, t), 10.11 (1H, s width), 11.31 (1H, s).

Example 15 2- [N- (2,4,5-Trimethoxybenzoyl) amino] -4 - [[2- [N- [2- (3,4-dimethoxyphenyl) ethyl] -N-methylamino] ethyl] aminocarbonyl] -1, 3-thiazole

MS (FAB, m / z): 559 (MH +)

IR (net) cm -1: 3300, 3250, 1655

1 H NMR (CDCl 3) δ: 2.38 (3H, s), 2.66-2.75 (4H, m), 3.53-3.56 (2H, m), 3.76-3.86 (2H, m), 3.80 (3H, s), 3.85 (3H, s), 3.91 (3H, s), 3.97 (3H, s), 4.04 (3H, s), 6.56 (1H, s), 6.75-6.82 (3H, m), 7.52 (1H, width), 7.74-7.75 (2H, m), 11.04 (1H, width).

Example 16 2- [N- (2,4,5-Trimethoxybenzoyl) amino] -4 - [[2- [N- (2-hydroxyethyl) -N-isopropylamino] ethyl] aminocarbonyl] -1,3-thiazole

MS (FAB, m / z): 467 (MH +)

IR (net) cm -1: 3322, 1655

1 H NMR (CDCl 3) δ: 1.05 (6H, d), 2.64 (2H, t), 2.30 (1H, width), 2.70 (2H, t), 3.02 (1H, quint.), 3.47 (2H, c), 3.61 (2H, t), 3.92 (3H, s), 3.99 (3H, s), 4.14 (3H, s), 6.58 (1H, s), 7.71 (1H, width), 7.74 (1H, s), 7.77 (1H, s), 11.20 (1H, wide s).

Example 17 2- [N- (2,4,5-Trimethoxybenzoyl) amino] -4 - [[2- (2-isooxazolinyl) ethyl] aminocarbonyl] -1,3-thiazole

MS (FAB, m / z): 249 (MH +)

IR (KBr) cm -1: 3312, 1732, 1662

1 H NMR (CDCl 3) δ: 2.35 (2H, quint.), 3.42 (2H, t), 3.76-3.81 (2H, m), 3.92 (3H, s), 3.99 (3H, s), 4.03 (3H, s), 4.16 (2H, t), 6.58 (1H, s), 7.77 (1H, s), 7.87 (1H, s), 11.12 (1H, s).

Example 18 2- [N- (2,4,5-Trimethoxybenzoyl) amino] -4 - [[2- (N-isopropylamino) ethyl] aminocarbonyl] -1,3-thiazole

MS (FAB, m / z): 423 (MH +)

IR (KBr) cm -1: 3220, 2959, 1659, 1608

1 H NMR (CDCl 3) δ: 1.09 (6H, d), 2.86 (3H, m), 3.54 (2H, dd), 3.93 (3H, s), 3.99 (3H, s), 4.13 (3H, s), 6.59 (1H, s), 7.55 (1H, t), 7.76 (1H, s), 7.78 (1H, s), 11.00 (1H, wide s).

Example 19 2- [N- (2,4,5-Trimethoxybenzoyl) amino] -4 - [[2- [N-ethoxycarbonylmethyl) -N-isopropyl] aminoethyl] aminocarbonyl] -1,3-thiazole

MS (FAB, m / z): 496 (MH +)

IR (net) cm -1: 3346, 1743, 1655

1 H NMR (CDCl 3) δ: 1.06 (6H, d), 1.26 (3H, t), 2.79 (2H, t), 3.06 (1H, quint.), 3.33 (2H, s), 3.48 (2H, c), 3.93 (3H, s), 3.99 (3H, s), 4.12 (3H, s), 4.23 (2H, c), 6.59 (1H, s), 7.75 (1H, s), 7.79 (1H, s), 7.89-7.91 (1H, m), 11.10 (1H, s).

Example 20 2- [N- (2,4,5-Trimethoxybenzoyl) amino] -4 - [[2- [N- (hydroxycarbonylmethyl) -N-isopropyl] aminoethyl] aminocarbonyl] -1,3-thiazole

MS (FAB, m / z): 467 (MH +)

IR (net) cm -1: 3307, 1655

1 H NMR (DMSO-d6) δ: 1.00 (6H, d), 2.88 (2H, t), 3.13 (1H, quint.), 3.15 (2H, s), 3.48-3.52 (2H, m), 3.78 (3H, s), 3.92 (3H, s), 4.05 (3H, s), 6.87 (1H, s), 7.48 (1H, s), 7.88 (1H, s), 8.53-8.56 (1H, m), 8.73-8.76 (1H, m), 12.23 (1H, width).

Example 21 Fumarate of 2- [N- (3,4-dimethoxybenzoyl) amino] -4 - [(3-dimethylaminopropyl) aminocarbonyl] -1,3-thiazole

MS (FAB, m / z): 393 (MH +)

IR (KBr) cm -1: 3389, 1695

1 H NMR (DMSO-d6) δ: 1.74 (2H, c), 2.33 (6H, s), 3.17 (2H, s), 3.32 (2H, c), 3.85 (3H, s), 3.87 (3H, s), 6.51 (1H, s), 7.11 (1H, d), 7.77 (2H, m), 7.97 (1H, t).

Example 22 Maleate 2- [N- (3,4-dimethoxybenzoyl) amino] -4- [2- (1-piperazinyl) ethylaminocarbonyl] -1,3-thiazole

A mixture of 10.0 g of 2- [N- (3,4-dimethoxybenzoyl) amino] -4- (ethoxycarbonyl) -1,3-thiazole obtained in Reference Example 1 and 15.4 g of 2- (1-Piperazinyl) ethylamine was stirred at 100 ° C for 2 hours The reaction mixture was subjected to distillation at reduced pressure To the residue, 10 ml of methanol was added. The crystals precipitated in this way were collected by filtration. After conversion into maleate, the resulting crystals are recrystallized from methanol, whereby 12.2 g of the title compound. Yield: 77%.

MS (FAB, m / z): 420 (MH +)

IR (KBr) cm -1: 3568, 3550, 3416, 1668

1 H NMR (DMSO-d_ {6}) δ: 2.49-2.63 (4H, m), 3.07-3.10 (2H, m), 3.31-3.46 (6H, m), 3.86 (3H, s), 3.87 (3H, s), 6.02 (2H, s), 7.12 (1H, d), 7.72-7.83 (4H, m), 8.47 (1H, width), 12.50 (1H, width), 13.00-14.00 (2H, width).

Example 23 Hydrochloride 2- [N- (3,4-dimethoxybenzoyl) amino] -4- [2- (4-methyl-1-piperazinyl) ethylaminocarbonyl] -1,3-thiazole

2.0 g of the compound obtained were dissolved in the Example 22 in the form of a free base in 30 ml of formic acid. TO the resulting solution, 950 mg of 35% formaldehyde was added, followed by stirring at 80 ° C for one hour. After letting it cool, The reaction mixture was subjected to distillation under reduced pressure. To the residue, 20 ml of ethanol was added, followed by the addition of a 4N hydrochloric acid-dioxane solution. The crystals precipitated in this way were collected by filtration. The crystals thus obtained were recrystallized from methanol, with which obtained 1.6 g of the title compound. Performance: 59%

MS (FAB, m / z): 434 (MH +)

IR (KBr) cm -1: 3280, 3200, 1655

1 H NMR (DMSO-d_ {6}) δ: 2.83 (3H, s), 3.38-3.71 (12H, m), 3.86 (3H, s), 3, 87 (3H, s), 7.12 (1H, d), 7.73-7.95 (3H, m), 8.31 (1H, width), 12.68 (1H, wide), 13.00-14.00 (1H, wide).

Example 24 Trihydrochloride 2- [N- (3,4-dimethoxybenzoyl) amino] -4- [2- [4- (2-hydroxyethyl) -1-piperazinyl) ethylaminocarbonyl] -1,3-thiazole

2.0 g of the compound obtained were suspended in Example 22 in the form of a free base in 30 ml of methanol. To resulting suspension, 1.4 g of aqueous solution of 40% glyoxal, followed by stirring at room temperature during 3 hours. After cooling with ice, to the mixture of reaction 400 mg of sodium borohydride was added. Mix The resulting was stirred at room temperature for 12 hours. To reaction mixture, 50 ml of water was added, followed by extraction with a mixed solution of chloroform and methanol. The layer Organic was washed with 2N hydrochloric acid. By adding potassium carbonate, the aqueous layer became alkaline, followed by extraction with a mixed solution of chloroform and methanol. After from drying through molecular sieves, the solvent was removed by distillation under reduced pressure. The residue was purified by chromatography on a silica gel column (chloroform: methanol = 20: 1). The compound thus obtained was dissolved in 20 ml of ethanol, followed by the addition of an acid solution 4N hydrochloric dioxane. The precipitated crystals that way they were collected by filtration, followed by recrystallization from ethanol, which resulted in 650 mg of title compound. Yield: 27%.

MS (FAB, m / z): 464 (MH +)

IR (KBr) cm -1: 3300, 3225, 1676

1 H NMR (DMSO-d_ {6}) δ: 2.38-2.53 (12H, m), 3.19-3.51 (5H, m), 3.86 (3H, s), 3, 87 (3H, s), 7.09 (1H, d), 7.52-7.77 (4H, m), 11.00-11.50 (1H, width), 13.00-14.00 (3H, width).

Example 25 2- [N- (3,4-Dimethoxybenzoyl) amino] -4- [2 - [(2-thiazolidinyliden) imino] ethylaminocarbonyl] -1,3-thiazole

A mixture of 5 g of the compound obtained in the Example 2 in the form of a free base and 5.7 g of 2-methylthiothiazoline was stirred at 150 ° C for one time. After allowing the reaction mixture to cool, it They added 50 ml of methanol. The crystals precipitated in this way they were collected by filtration, whereby 3.63 g of the title compound. Yield: 58%.

MS (FAB, m / z): 436 (MH +)

IR (KBr) cm -1: 3400, 3000, 1642

1 H NMR (CH 3 OD) δ: 3.56-3.66 (6H, m), 3.94 (6H, s), 4.01 (2H, t), 7.10 (1H, d), 7.63 (1H, d), 7.69 (1H, dd), 7.82 (1H, s).

In a manner similar to Example 25, they prepared the compounds of Example 26 to 28.

Example 26 Hydroiodide 2- [N- (3,4-Dimethoxybenzoyl) amino] -4- [2 - [(2-pyrrolidiniden) imino] ethylaminocarbonyl] -1,3-thiazole

MS (FAB, m / z): 418 (MH +)

IR (KBr) cm -1: 3420, 3083, 1649, 1618

1 H NMR (DMSO-d6) δ: 2.03 (2H, c), 2.78 (2H, t),  3.41-3.63 (6H, m), 3.85 (3H, s), 3.86 (3H, s), 7.12 (1H, d), 7.71 (1H, d), 7.76 (1H, dd), 7.86 (1H, s), 8.06 (1H, s width), 9.55 (2H, wide s), 12.57 (1H, wide s).

Example 27 2- [N- (3,4-Dimethoxybenzoyl) amino] -4- [2 - [(2-oxazolidiniden) imino] ethylaminocarbonyl] -1,3-thiazole

MS (FAB, m / z): 420 (MH +)

IR (KBr) cm -1: 3380, 2910, 1643

1 H NMR (DMSO-d6) δ: 3.34 (2H, t), 3.54 (2H, t),   3.70 (2H, t), 3.92 (3H, s), 3.93 (3H, s), 4.29 (2H, t), 7.08 (1H, d), 7.63 (1H, d), 7.68 (1H, c), 7.76 (1H, s).

Example 28 Hydrochloride 2- [N- (3,4-Dimethoxybenzoyl) amino] -4- [2 - [(2-imidazolidiniden) imino] ethylaminocarbonyl] -1,3-thiazole

MS (FAB, m / z): 419 (MH +)

IR (KBr) cm -1: 3389, 3197, 1676

1 H NMR (DMSO-d6) δ: 3.17 (1H, s), 3.31 (2H, m),  3.40 (2H, wide s), 3.57 (4H, s), 3.78 (3H, s), 3.79 (3H, s), 6.92 (1H, d), 7.26 (1H, s), 7.68 (2H, m), 8.31 (1H, width).

Example 29 Dihydrochloride 2- [N- (3,4-dimethoxybenzoyl) amino] -4 - [(4-dimethylaminobutyl) aminocarbonyl] -1,3-thiazole

5 g of the compound obtained in the Example of Reference 1, 13.1 g of 1,4-butanediamine, followed by stirring at 100 ° C for 2 hours The reaction mixture was subjected to distillation at reduced pressure To the residue, water was added. The resulting mixture it was extracted with a mixed solution of chloroform and methanol, followed drying through molecular sieves. Then the solvent is distilled off, whereby 4.5 g of 2- [N- (3,4-dimethoxybenzoyl) amino] -4 - [(4-aminobutyl) aminocarbonyl] -1,3-thiazole.

Then, the compound thus obtained was dissolved in 45 ml formic acid. Cooling with ice, 2.3 g of a 35% aqueous solution of formaldehyde to the resulting solution, followed by reflux for one hour. Once the mix of reaction was subjected to distillation under reduced pressure, the residue was neutralized with an aqueous bicarbonate solution of sodium, followed by extraction with a mixed solution of chloroform and methanol The extract was dried through molecular sieves and the solvent was distilled off under reduced pressure. The residue thus obtained was purified by gel column chromatography of silica (chloroform: methanol = 50: 1), whereby 1.0 g were obtained of the title compound in the form of a free base. The compound is converted into its dihydrochloride and thus, the title compound.

MS (FAB, m / z): 407 (MH +)

IR (KBr) cm -1: 3350, 3245, 1601

1 H NMR (DMSO-d6) δ: 1.55 (2H, m), 1.64 (2H, m),  2.70 (3H, s), 2.72 (3H, s), 3.03 (2H, m), 3.30 (2H, m), 3.85 (3H, s), 3.87 (3H, s), 7.12 (1H, d), 7.37-7.80 (2H, m), 7.85 (1H, s), 7.97 (1H, t), 10.48 (1H, width), 12.64 (1H, width).

Example 30 2- [N- (2,4,5-Trimethoxybenzoyl) amino] -4 - [(2-dimethylaminoethoxy) carbonyl] -1,3-thiazole

In 10 ml of N, N-dimethylformamide, 278 mg of sodium hydride were suspended. To the suspension resulting, 620 mg of N, N-dimethylaminoethanol, followed by stirring room temperature for one hour. In another 10 ml portion of N, N-dimethylformamide, 1.57 g of 2- [N- (2,4,5-trimethoxybenzoyl) amino] -4- (hydroxycarbonyl) -1,3-thiazole. To the resulting suspension, 827 mg of carbonyldiimidazole, followed by stirring at room temperature for an hour. The two reaction mixtures obtained in this way they were combined and stirred at 100 ° C for one hour. The mixture of reaction was poured into ice water and the precipitated crystals of This mode was collected by filtration. The crystals obtained from this mode was recrystallized from isopropyl alcohol, so that they obtained 1.4 g of the title compound. Yield: 74%.

MS (FAB, m / z): 410 (MH +)

IR (KBr) cm -1: 3316, 1727, 1655

1 H NMR (CDCl 3) δ: 2.35 (6H, s), 2.73 (2H, t), 3.92 (3H, s), 3.99 (3H, s), 4.10 (3H, s), 4.46 (2H, t), 6.58 (1H, s), 7.77 (1H, s), 7.86 (1H, t), 11.14 (1H, wide s).

In a manner similar to Example 30, prepared the compounds of Example 31 to 33 that will be described more ahead.

Example 31 2- [N- (2,4,5-Trimethoxybenzoyl) amino] -4 - [(2-diethylaminoethoxy) carbonyl] -1,3-thiazole

MS (FAB, m / z): 438 (MH +)

IR (KBr) cm -1: 3308, 1721, 1659

1 H NMR (CDCl 3) δ: 1.07 (6H, t), 2.63 (4H, c), 2.86 (2H, t), 3.92 (3H, s), 3.98 (3H, s), 4.09 (3H, s), 4.42 (2H, t), 6.58 (1H, s), 7.77 (1H, s), 7.83 (1H, s), 11.13 (1H, wide s).

Example 32 2- [N- (2,4,5-Trimethoxybenzoyl) amino] -4 - [(2-diisopropylaminoethoxy) carbonyl] -1,3-thiazole

MS (FAB, m / z): 466 (MH +)

IR (KBr) cm -1: 3306, 1721, 1655

1 H NMR (CDCl 3) δ: 1.04 (12H, t), 2.63 (4H, c), 2.86 (2H, t), 3.92 (3H, s), 3.98 (3H, s), 4.09 (3H, s), 4.42 (2H, t), 6.58 (1H, s), 7.77 (1H, s), 7.83 (1H, s), 11.13 (1H, wide s).

Example 33 2- [N- (3,4-Dimethoxybenzoyl) amino] -4 - [(2-dimethylaminoethoxy) carbonyl] -1,3-thiazole

MS (FAB, m / z): 380 (MH +)

IR (KBr) cm -1: 3245, 1738, 1680

1 H NMR (CDCl 3) δ: 2.31 (6H, s), 2.68 (2H, t), 3.94 (3H, s), 3.96 (3H, s), 4.38 (2H, t), 6.94 (1H, d), 7.48-7.53 (2H, m), 7.87 (1H, s), 9.50 (1H, wide s).

In a manner similar to Reference Example 1, except that chloride was replaced 3,4-dimethoxybenzoyl by the corresponding chloride of benzoyl substituted in position 3, an intermediate was prepared. From in a manner similar to Example 2, the compounds of the Examples 34 to 41, which will be described below, using the intermediate thus obtained.

Example 34 Dihydrochloride 2- [N- (2-amino-4,5-dimethoxybenzoyl) amino] -4 - [(2-dimethylaminoethyl) aminocarbonyl] -1,3-thiazole

MS (FAB, m / z): 394 (MH +)

IR (KBr) cm -1: 3393, 2995, 1655, 1526, 1296

1 H NMR (DMSO-d6) δ: 2.80 (3H, s), 2.82 (3H, s),  3.26 (2H, c), 3.68 (2H, c), 3.80 (3H, s), 3.82 (3H, s), 4.40-6.40 (4H, width), 6.83 (1H, s), 7.53 (1H, s), 7.98 (1H, s), 8.43 (1H, t), 10.59 (1H, broad s).

Example 35 2- [N- (4,5-Dimethoxy-2-nitrobenzoyl) amino] -4 - [(2-dimethylaminoethyl) aminocarbonyl] -1,3-thiazole

MS (FAB, m / z): 424 (MH +)

IR (KBr) cm -1: 3428, 1663, 1549, 1522, 1298

\hbox{(1H, s).}

1 H NMR (DMSO-d 6) δ: 2.20 (6H, s), 2.43 (2H, t), 3.37 (2H, c), 3.93 (6H , s), 7.36 (1H, s), 7.70 (2H, m), 7.84

 \ hbox {(1H, s).} 

Example 36 2- [N- (2-Bromo-4,5-dimethoxybenzoyl) amino] -4 - [(2-dimethylaminoethyl) aminocarbonyl] -1,3-thiazole

MS (FAB, m / z): 457 (MH +)

IR (KBr) cm -1: 3410, 1672, 1657, 1545, 1507, 1269

1 H NMR (CDCl 3) δ: 2.22 (6H, s), 2.57 (2H, t), 3.54 (2H, c), 3.91 (3H, s), 3.94 (3H, s), 7.09 (1H, s), 7.36 (1H, s), 7.57 (1H, t), 7.76 (1H, s).

Example 37 2- [N- (4,5-Dimethoxy-2-hydroxybenzoyl) amino] -4 - [(2-dimethylaminoethyl) aminocarbonyl] -1,3-thiazole

MS (FAB, m / z): 395 (MH +)

IR (KBr) cm -1: 3401, 1655, 1549, 1491, 1244, 1217, 1206

1 H NMR (CDCl 3) δ: 2.58 (6H, s), 2.93 (2H, t), 3.48 (2H, c), 3.72 (3H, s), 3.75 (3H, s), 6.43 (1H, s), 7.42 (1H, s), 7.59 (1H, s), 8.25 (1H, t).

Example 38 2- [N- (4,5-Dimethoxy-2-hydroxybenzoyl) amino] -4 - [(2-diisopropylaminoethyl) aminocarbonyl] -1,3-thiazole

A mixture of 15.4 g of acetate 2- [N- (4,5-dimethoxy-2-hydroxybenzoyl) amino] -4- (ethoxycarbonyl) -1,3-thiazole obtained in Reference Example 6 and 26.9 g of diisopropylethylenediamine was stirred at 120 ° C for 30 minutes in a Argon gas stream. The reaction mixture was subjected to distillation under reduced pressure. To the residue, chloroform was added for dilution, followed by washing with water. The chloroform layer dried over sodium sulfate. The solvent was removed by distillation under reduced pressure, whereby 11.7 g of the title compound. Yield: 69%.

MS (FAB, m / z): 451 (MH +)

IR (KBr) cm -1: 3401, 1661, 1522, 1267

1 H NMR (DMSO-d6) δ: 1.32 (12H, m), 3.16 (2H, m), 3.63 (4H, m), 3.77 (3H, s), 3.82 (3H, s), 6.84 (1H, s), 7.50 (1H, s), 7.89 (1H, s), 8.71 (1H, t), 9.56 (1H, width), 11.79 (1H, s width), 12.00 (1H, width).

In addition, 11.7 g of the compound of the title in isopropyl alcohol. Hydrochloric acid was passed gas by the resulting solution cooling. The crystals precipitates thus collected by filtration, followed by recrystallization from a solvent mixture of isopropyl alcohol and water, whereby 14.0 g of the compound hydrochloride were obtained of the title.

Example 39 Dihydrochloride 2- [N- (4,5-dimethoxy-2-dimethylaminobenzoyl) amino] -4 - [(2-dimethylaminoethyl) aminocarbonyl] -1,3-thiazole

MS (FAB, m / z): 422 (MH +)

IR (KBr) cm -1: 3410, 1526, 1422, 1339, 1294

1 H NMR (DMSO-d_ {6}) δ: 2.81 (3H, s), 2.83 (3H, s), 3.12 (6H, s), 3.28 (2H, c), 3.68 (2H, c), 3.94 (3H, s), 4.80 (3H, s), 7.49 (1H, s), 7.67 (1H, s), 8.05 (1H, s), 8.99 (1H, wide s), 10.70 (1H, wide s).

Example 40 2- [N- (4,5-Dimethoxy-2-methylbenzoyl) amino] -4 - [(2-dimethylaminoethyl) aminocarbonyl] -1,3-thiazole

MS (FAB, m / z): 393 (MH +)

IR (KBr) cm -1: 3474, 2983, 1674, 1561, 1271, 1146

1 H NMR (CDCl 3) δ: 2.15 (6H, s), 2.50 (3H, s), 2.55 (2H, t), 3.53 (2H, c), 3.91 (3H, s), 3.93 (3H, s), 6.76 (1H, s), 7.22 (1H, s), 7.62 (1H, t), 7.71 (1H, s).

Example 41 2- [N- (4,5-Dimethoxy-2-acetylaminobenzoyl) amino] -4 - [(2-dimethylaminoethyl) aminocarbonyl] -1,3-thiazole

MS (FAB, m / z): 436 (MH +)

IR (KBr) cm -1: 3565, 1650, 1555, 1534, 1292

1 H NMR (CDCl 3) δ: 2.24 (9H, s), 2.57 (2H, t), 3.50 (2H, c), 3.76 (3H, s), 3.99 (3H, s), 7.38 (1H, s), 7.62 (1H, t), 7.74 (1H, s), 8.43 (1H, s).

Example 42 Hydrochloride 2- [N- (benzoyl) amino] -4 - [(2-dimethylaminoethyl) aminocarbonyl] -1,3-thiazole

MS (EI, m / z): 318 (M +)

IR (KBr) cm -1: 3400, 1669, 1644

1 H NMR (DMSO-d_ {6}) δ: 2.81 (6H, d), 3.24-3.30 (2H, m), 3.65-3.72 (2H, m), 7.53-7.70 (3H, m), 8.00-8.41 (4H, m), 10.58 (1H, wide s), 12.84 (1H, s).

Example 43 Maleate 2- [N- (2-methoxybenzoyl) amino] -4 - [(2-dimethylaminoethyl) aminocarbonyl] -1,3-thiazole

IR (KBr) cm -1: 3320, 3050, 1660, 1610, 1570, 1540

1 H NMR (DMSO-d6) δ: 2.83 (6H, s), 2.76 (2H, c), 3.61 (2H, c), 3.98 (3H, s), 6.02 (2H, s), 7.13 (1H, t), 7.27 (1H, d), 7.58-7.63 (2H, m), 7.84 (1H, dd), 7.93 (1H, s), 9.30 (2H, wide s), 11.67 (1H, s).

Example 44 Dihydrochloride 2- [N- (3-methoxybenzoyl) amino] -4 - [(2-dimethylaminoethyl) aminocarbonyl] -1,3-thiazole

IR (KBr) cm -1: 3400, 3200, 2966, 2689, 1690, 1670, 1580, 1560, 1520

1 H NMR (DMSO-d6) δ: 2.80 (3H, s), 2.82 (3H, s), 3.26 (2H, c), 3.68 (3H, s), 6.91 (1H, wide s), 7.71-7.24 (1H, m), 7.47 (1H, t), 7.65-7.70 (2H, m), 8.01 (1H, s), 8.39 (1H, t), 10.68 (1H, wide s), 12.84 (1H, wide s).

Example 45 Maleate 2- [N- (3-Chlorobenzoyl) amino] -4 - [(2-dimethylaminoethyl) aminocarbonyl] -1,3-thiazole

IR (KBr) cm -1: 3300, 1669, 1659, 1541

1 H NMR (DMSO-d_ {6}) δ: 2.83 (6H, s), 3.24 (2H, t), 3.31 (3H, broad s), 3.63 (2H, m), 6.02 (2H, s), 7.60 (1H, t), 7.72 (1H, m), 7.93 (1H, s), 8.04 (1H, m), 8.15 (1H, m), 8.21 (1H, t).

Example 46 Dihydrochloride 2- [N- (4-methoxybenzoyl) amino] -4 - [(2-dimethylaminoethyl) aminocarbonyl] -1,3-thiazole

IR (KBr) cm -1: 3400, 3150, 3050, 2950, 2700, 1670, 1655, 1603

1 H NMR (DMSO-d6) δ: 2.80 (3H, s), 2.82 (3H, s), 3.25 (2H, c), 3.68 (2H, c), 3.85 (3H, s), 4.68 (1H, s), 7.05-7.15 (2H, m), 7.96 (1H, s), 8.01-8.15 (2H, m), 8.36 (1H, t), 10.54 (1H, s), 12.64 (1H, s).

Example 47 Maleate 2- [N- (2,3-dimethoxybenzoyl) amino] -4 - [(2-dimethylaminoethyl) aminocarbonyl] -1,3-thiazole

MS (EI, m / z): 318 (M +)

IR (KBr) cm -1: 3403, 3297, 1671, 1580

1 H NMR (DMSO-d_ {6}) δ: 2.83 (6H, s), 3.25 (2H, t), 3.61 (2H, c), 3.88 (3H, s), 3.89 (3H, s), 6.02 (2H, s), 7.20-7.33 (3H, m), 7.91 (1H, s), 8.35 (1H, t), 9.00-10.00 (2H, wide), 12.00 (1H, wide s).

Example 48 Maleate 2- [N- (2-hydroxy-3-methoxybenzoyl) amino] -4 - [(2-dimethylaminoethyl) aminocarbonyl] -1,3-thiazole

MS (EI, m / z): 304 (M +)

IR (KBr) cm -1: 3400, 1660, 1551

1 H NMR (DMSO-d_ {6}) δ: 2.83 (6H, s), 3.26 (2H, t), 3.60 (2H, c), 3.89 (3H, s), 6.03 (2H, s), 6.94 (1H, t), 7.22 (1H, dd), 7.59 (1H, dd), 7.85 (1H, s), 8.54 (1H, t), 9.00-12.00 (3H, width).

Example 49 Dihydrochloride 2- [N- (4-hydroxy-2-methoxybenzoyl) amino] -4 - [(2-diisopropylaminoethyl) aminocarbonyl] -1,3-thiazole

1 H NMR (DMSO-d_ {6}) δ: 1.29-1.33 (12H, m), 2.47-2.51 (2H, m), 3.19-3.58 (4H, m), 3.59-3.76 (2H, m), 3.97 (3H, s), 6.82 (1H, s), 7.87 (1H, s), 7.90 (1H, s), 8.53-8.68 (1H, m), 9.09-9.23 (1H, m), 11.28 (1H, s), 11.41 (1H, s).

Example 50 2- [N- (2-Hydroxy-4-methoxybenzoyl) amino] -4 - [(2-diisopropylaminoethyl) aminocarbonyl] -1,3-thiazole

1 H NMR (CDCl 3) δ: 1.22 (12H, d), 2.88-2.91 (2H, m), 3.25-3.31 (2H, m), 3.61-3.65 (2H, m), 3.82 (3H, s), 6.41-6.50 (2H, m), 7.69 (1H, s), 7.81-7.84 (1H, m), 8.07 (1H, d), 10.82 (1H, s), 11.43 (1H, s).

Example 51 Maleate 2- [N- (2,5-Dimethoxybenzoyl) amino] -4 - [(2-dimethylaminoethyl) aminocarbonyl] -1,3-thiazole

MS (EI, m / z): 378 (M +)

IR (KBr) cm -1: 3305, 1661

1 H NMR (DMSO-d_ {6}) δ: 2.84 (6H, s), 3.26 (2H, t), 3.61 (2H, c), 3.79 (3H, s), 3.96 (3H, s), 6.02 (2H, s), 7.18-7.43 (3H, m), 7.91 (1H, s), 8.43 (1H, t), 8.50-11.00 (2H, width).

Example 52 Maleate 2- [N- (2,6-Dimethoxybenzoyl) amino] -4 - [(2-dimethylaminoethyl) aminocarbonyl] -1,3-thiazole

MS (EI, m / z): 318 (M +)

IR (KBr) cm -1: 3303, 1661, 1599

1 H NMR (DMSO-d6) δ: 2.81 (6H, s), 3.23 (2H, t), 3.61 (2H, c), 3.76 (6H, s), 6.02 (2H, s), 6.75 (2H, d), 7.40 (1H, t), 7.85 (1H, s), 8.13 (1H, t), 9.00-9.50 (2H, wide), 12.40 (1H, wide s).

Example 53 Hydrochloride 2- [N- (3,5-Dimethoxybenzoyl) amino] -4 - [(2-dimethylaminoethyl) aminocarbonyl] -1,3-thiazole

IR (KBr) cm -1: 3600, 3250, 3100, 1650, 1637, 1601

1 H NMR (DMSO-d6) δ: 2.80 (3H, s), 2.82 (3H, s),  3.30-3.60 (2H, m), 3.60-3.75 (2H, m), 3.83 (6H, s), 6.75 (1H, s), 7.28 (1H, s), 7.29 (1H, s), 7.99 (1H, s), 8.30-8.40 (1H, m), 10.38 (1H, wide s), 12.79 (1H, s).

Example 54 Dihydrochloride 2- [N- (3,4-dimethoxybenzoyl) amino] -4 - [(2-methylaminoethyl) aminocarbonyl] -1,3-thiazole

IR (KBr) cm -1: 3450, 1674, 1601, 1560

1 H NMR (DMSO-d 6) δ: 2.57 (3H, t), 3.08 (2H, t), 3.63 (2H, c), 3.86 (3H, s), 3.87 (3H, s), 4.88 (1H, wide s), 7.12 (1H, d), 7.74-7.80 (2H, m), 7.96 (1H, s), 8.28 (1H, t), 9.11 (2H, wide s), 12.70 (1H, wide s).

Example 55 Dihydrochloride 2- [N- (3,4-dimethoxybenzoyl) amino] -4- [N- (2-methylaminoethyl) -N-methylaminocarbonyl] -1,3-thiazole

IR (KBr) cm -1: 3450, 1680, 1636, 1559, 1279

1 H NMR (CD 3 OD) δ: 3.20 (6H, s), 3.88 (3H, s), 3.91 (3H, s), 3.99 (4H, s), 6.99 (1H, d), 7.59 (1H, s), 7.80 (1H, dd), 7.84 (1H, d).

Example 56 Maleate 2- [N- (3,4-dimethoxybenzoyl) amino] -4 - [(2-isopropylaminoethyl) aminocarbonyl] -1,3-thiazole

1 H NMR (CDCl 3) δ: 1.42 (6H, d), 3.26-3.39 (2H, m), 3.45-3.52 (1H, m), 3.68-3.51 (1H, m), 3.68-3.79 (2H, m), 3.89 (3H, s), 3.93 (3H, s), 6.26 (2H, s), 6.94-6.97 (1H, m), 7.58 (1H, s), 7.59 (1H, s), 7.93 (1H, d), 8.84-8.91 (1H, m), 9.39 (2H, s), 11.10 (1H, s).

Example 57 Dihydrochloride 2- [N- (4-hydroxy-3-methoxybenzoyl) amino] -4 - [(2-diisopropylaminoethyl) aminocarbonyl] -1,3-thiazole

1 H NMR (DMSO-d_ {6}) δ: 1.30-1.37 (12H, m), 3.16-3.20 (2H, m), 3.59-3.67 (4H, m), 3.82 (1H, s), 3.87 (3H, s), 6.91-6.94 (1H, m), 7.61-7.65 (1H, m), 7.72 (1H, s), 7.91 (1H, s), 8.40-8.45 (1H, m), 9.97-9.99 (2H, m), 12.55 (1H, s).

Example 58 Dihydrochloride 2- [N- (3-hydroxy-4-methoxybenzoyl) amino] -4 - [(2-diisopropylaminoethyl) aminocarbonyl] -1,3-thiazole

1 H NMR (DMSO-d_ {6}) δ: 1.30-1.37 (12H, m), 3.13-3.18 (2H, m), 3.57 (1H, s), 3.56-3.65 (4H, m), 3.86 (3H, s), 7.04-7.07 (1H, m), 7.51 (1H, s), 7.63-7.67 (1H, m), 7.90 (1H, s), 8.41-8.50 (1H, m), 9.94-9.99 (2H, m), 12.51 (12.51 (1H, s).

Example 59 Hydrochloride 2- [N- (3,4-dimethoxybenzoyl) amino] -4 - [[2- (N-2-pyridylamino) ethyl] aminocarbonyl] -1,3-thiazole

MS (FAB, m / z): 428 (MH +)

1 H NMR (DMSO-d_ {6}) δ: 3.60 (2H, broad s), 3.76 (2H, wide s), 3.85 (3H, s), 3.87 (3H, s), 6.82-6.87 (1H, m), 7.08-7.14 (2H, m), 7.73-7.79 (2H, m), 7.85-7.92 (2H, m), 8.10 (1H, wide s), 9.09 (1H, wide s), 12.67 (1H, s wide), 14.09 (2H, wide s).

Example 60 Maleate 2- [N- (3,4-dimethoxybenzoyl) amino] -4 - [[2- (1-pyrrolidyl) ethyl] aminocarbonyl] -1,3-thiazole

MS (FAB, m / z): 405 (MH +)

IR (KBr) cm -1: 3450, 1669, 1545, 1515

1 H NMR (CD 3 OD) δ: 2.10 (4H, broad s), 3.30-3.32 (4H, m), 3.46 (2H, t), 3.87 (2H, t), 3.92 (3H, s), 3.93 (3H, s), 6.23 (2H, s), 7.09 (1H, d), 7.61 (1H, d), 7.68 (1H, dd), 7.83 (1H, s).

Example 61 Dihydrochloride 2- [N- (3,4-dimethoxybenzoyl) amino] -4 - [[2- (1-piperidinyl) ethyl] aminocarbonyl] -1,3-thiazole

MS (FAB, m / z): 419 (MH +)

IR (KBr) cm -1: 3300, 1675, 1665, 1605, 1555, 1534

1 H NMR (CD 3 OD) δ: 1.45-2.05 (6H, m), 2.90-3.10 (2H, m), 3.41 (2H, t), 3.63-3.81 (4H, m), 3.93 (6H, s), 6.26 (2H, s), 7.10 (1H, d), 7.61 (1H, d), 7.69 (1H, dd), 7.84 (1H, s).

Example 62 2- [N- (3,4-Dimethoxybenzoyl) amino] -4 - [[2- (2-pyrrolidon-1-yl) ethyl] aminocarbonyl] -1,3-thiazole

IR (KBr) cm -1: 3411, 1684, 1650, 1603

1 H NMR (DMSO-d_ {6}) δ: 1.91 (2H, quint.), 2.18 (2H, t), 3.30-3.50 (6H, m), 3.85 (3H, s), 3.87 (3H, s), 7.11 (1H, d), 7.70-7.80 (2H, m), 7.83 (1H, s), 7.91 (1H, t), 12.63 (1H, s).

Example 63 2- [N- (3,4-Dimethoxybenzoyl) amino] -4 - [[2- (2-piperidon-1-yl) ethyl] aminocarbonyl] -1,3-thiazole

IR (KBr) cm -1: 3450, 1650, 1613, 1551, 1518

1 H NMR (DMSO-d_ {6}) δ: 1.60-1.80 (4H, m), 2.18 (2H, t), 3.25-3.40 (2H, m), 3.40-3.50 (4H, m), 3.85 (3H, s), 3.87 (3H, s), 7.11 (1H, d), 7.70-7.79 (3H, m), 7.80 (1H, s), 7.95 (1H, s width).

Example 64 Hydrochloride 2- [N- (3,4-dimethoxybenzoyl) amino] -4 - [(2-guanidinoethyl) aminocarbonyl] -1,3-thiazole

MS (FAB, m / z): 393 (MH +)

IR (KBr) cm -1: 3160, 1663, 1603, 1565, 1532

1 H NMR (DMSO-d_ {6}) δ: 3.32-3.46 (4H, m), 3.86 (3H, s), 3.87 (3H, s), 6.52 (2H, wide s), 7.10-7.65 (3H, m), 7.73-7.79 (2H, m), 7.86-7.90 (2H, m), 8.03-8.07 (1H, m), 12.67 (1H, wide s).

Example 65 Dihydrochloride 2- [N- (3,4-dimethoxybenzoyl) amino] -4- [2- [3- (1-methylthioureido) ethyl) aminocarbonyl] -1,3-thiazole

1 H NMR (DMSO-d_ {6}) δ: 2.79-2.98 (2H, m), 3.57 (3H, s), 3.62-3.73 (2H, m), 3.85 (3H, s), 3.86 (3H, s), 5.19-5.74 (2H, m), 7.12 (1H, s), 7.73-7.78 (2H, m), 7.94 (1H, s), 8.19-8.29 (1H, m), 8.92-9.08 (1H, m), 10.02-10.31 (1H, m), 12.49-12.78 (1H, m). 7.73-7.79 (2H, m), 7.86-7.90 (2H, m), 8.03-8.07 (1H, m), 12.67 (1H, wide s).

Example 66 Dihydrochloride 2- [N- (3,4-dimethoxybenzoyl) amino] -4 - [[2- [3- (1,2-dimethyl) thioureido] ethyl] aminocarbonyl] -1,3-thiazole

1 H NMR (CDCl 3) δ: 2.38 (3H, s), 2.95 (3H, s), 3.47-3.53 (2H, m), 3.58-3.63 (2H, m), 3.97 (6H, s), 5.55 (4H, s width), 6.96-6.99 (1H, m), 7.66-7.74 (4H, m).

Example 67 Maleate 2- [N- (2,3,4-trimethoxybenzoyl) amino] -4 - [(2-dimethylaminoethyl) aminocarbonyl] -1,3-thiazole

IR (KBr) cm -1: 3400, 3300, 1660

1 H NMR (DMSO-d6) δ: 2.82 (6H, s), 3.24 (2H, t), 3.58 (2H, c), 3.82 (3H, s), 3.89 (3H, s), 3.99 (3H, s), 6.01 (2H, s), 7.03 (1H, d), 7.65 (1H, d), 7.89 (1H, s), 8.44 (1H, t), 9.25 (2H, wide s), 11.56 (1H, s).

Example 68 Maleate 2- [N- (2,3,5-trimethoxybenzoyl) amino] -4 - [(2-dimethylaminoethyl) aminocarbonyl] -1,3-thiazole

MS (EI, m / z): 348 (M +)

IR (KBr) cm -1: 3306, 1667, 1607

1 H NMR (DMSO-d_ {6}) δ: 2.83 (6H, s), 3.25 (2H, t), 3.61 (2H, c), 3.80 (3H, s), 3.81 (3H, s), 3.87 (3H, s), 6.02 (2H, s), 6.85 (1H, d), 6.88 (1H, d), 7.92 (1H, s), 8.37 (1H, t), 9.00-9.50 (2H, wide), 11.98 (1H, wide s).

Example 69 Maleate 2- [N- (2,3,6-trimethoxybenzoyl) amino] -4 - [(2-dimethylaminoethyl) aminocarbonyl] -1,3-thiazole

MS (EI, m / z): 348 (M +)

IR (KBr) cm -1: 3000, 1682, 1650

1 H NMR (DMSO-d_6) δ: 2.82 (6H, s), 3.23 (2H, t), 3.61 (2H, c), 3.72 (3H, s), 3.74 (3H, s), 3.80 (3H, s), 6.02 (2H, s), 6.80 (1H, d), 7.11 (1H, d), 7.87 (1H, s), 8.15 (1H, t), 8.80-10.00 (2H, wide), 12.51 (1H, wide s).

Example 70 Maleate 2- [N- (2,4,6-Trimethoxybenzoyl) amino] -4 - [(2-dimethylaminoethyl) aminocarbonyl] -1,3-thiazole

IR (KBr) cm -1: 3400, 2360, 1670

1 H NMR (CDCl 3) δ: 2.84 (6H, s), 3.25 (2H, t), 3.61 (2H, t), 3.76 (6H, s), 3.83 (3H, s), 6.01 (2H, s), 6.30 (2H, s), 7.82 (1H, s), 8.13 (1H, t), 9.25 (2H, wide s), 12.24 (1H, s).

Example 71 Fumarate of 2- [N- (3,4,5-Trimethoxybenzoyl) amino] -4- (2-dimethylaminoethyl) aminocarbonyl] -1,3-thiazole

IR (KBr) cm -1: 3300, 1670, 1590, 1550

1 H NMR (DMSO-d6) δ: 2.31 (6H, s), 2.58 (2H, t), 3.46 (2H, c), 3.76 (3H, s), 3.89 (6H, s), 6.58 (2H, s), 7.49 (2H, s), 7.81 (1H, t), 7.85 (1H, s).

Example 72 2- [N- (2,4,5-Trimethoxybenzoyl) amino] -4 - [(2-cyclopropylaminoethyl) aminocarbonyl] -1,3-thiazole

MS (FAB, m / z): 421 (MH +)

IR (KBr) cm -1: 1653, 1512, 1259, 1024

1 H NMR (CDCl 3) δ: 0.36-0.53 (4H, m), 2.20 (1H, ddd), 2.97 (2H, t), 3.56 (2H, c), 3.93 (3H, s), 4.00 (3H, s), 4.14 (3H, s), 6.59 (1H, s), 7.48 (1H, t), 7.76 (1H, s), 7.78 (1H, s), 11.05 (1H, s).

Example 73 Dihydrochloride 2- [N- (2,4,5-Trimethoxybenzoyl) amino] -4 - [(2-t-butylaminoethyl) aminocarbonyl] -1,3-thiazole

1 H NMR (DMSO-d_ {6}) δ: 1.30 (9H, s), 2.98-3.09 (2H, m), 3.17 (1H, s), 3.53-3.70 (2H, m), 3.78 (3H, s), 3.93 (3H, s), 4.08 (3H, s), 6.89 (1H, s), 7.50 (1H, s), 7.90 (1H, s), 8.49-8.63 (1H, m), 8.82-9.00 (2H, m), 11.32 (1H, s).

Example 74 Dihydrochloride 2- [N- (2,4,5-Trimethoxybenzoyl) amino] -4 - [(3-diisopropylaminopropyl) aminocarbonyl] -1,3-thiazole

MS (FAB, m / z): 479 (MH +)

IR (KBr) cm -1: 3410, 1674, 1663, 1611, 1584, 1553, 1520

1 H NMR (CDCl 3) δ: 1.27-1.34 (12H, m), 2.00-2.06 (2H, m), 3.06-3.10 (2H, m), 3.29-3.36 (2H, m), 3.56-3.62 (2H, m), 3.78 (3H, s), 3.93 (3H, s), 4.07 (3H, s), 6.88 (1H, s), 7.49 (1H, s), 7.87 (1H, s), 8.47 (1H, wide s), 9.92 (2H, s width).

Example 75 Maleate 2- [N- (2,4,5-trimethoxybenzoyl) amino] -4 - [[N- (2-diethylaminoethyl) -N-methyl] aminocarbonyl] -1,3-thiazole

IR (KBr) cm -1: 3400, 3320, 1640, 1625

1 H NMR (CDCl 3) δ: 1.23 (6H, t), 3.14 (3H, s), 3.15 (2H, c), 3.29 (2H, t), 3.76 (3H, s), 3.77 (4H, c), 3.92 (3H, s), 4.03 (3H, s), 6.02 (2H, s), 6.86 (1H, s), 7.49 (1H, s), 7.65 (1H, s), 9.50 (2H, wide s), 11.26 (1H, s).

Example 76 Maleate 2 - [[N-methyl-N- (2,4,5-trimethoxybenzoyl) amino] -4 - [(2-dimethylaminoethyl) aminocarbonyl] -1,3-thiazole

IR (KBr) cm -1: 3300, 1655

1 H NMR (CDCl 3) δ: 2.91 (6H, s), 3.33-3.38 (2H, m), 3.55 (3H, s), 3.81-3.99 (2H, m), 3.84 (3H, s), 3.88 (3H, s), 3.96 (3H, s), 6.16 (2H, s), 6.55 (1H, s), 6.95 (1H, s), 7.83 (1H, s), 8.12 (1H, t), 12.50 (2H, broad s).

Example 77 Maleate 2 - [[N-methyl-N- (2,4,5-trimethoxybenzoyl) amino] -4 - [(2-diisopropylaminoethyl) aminocarbonyl] -1,3-thiazole

IR (KBr) cm -1: 3300, 1655, 1541

1 H NMR (CDCl 3) δ: 1.37 (6H, d), 1.41 (6H, d), 3.25-3.35 (2H, m), 3.52 (3H, s), 3.58-3.68 (2H, m), 3.85 (3H, s), 3.86 (3H, s), 3.83-3.89 (2H, m), 3.97 (3H, s), 6.26 (2H, s), 6.56 (1H, s), 6.91 (1H, s), 7.82 (1H, s), 8.88 (1H, t), 10.70 (1H, s).

Example 78 Dihydrochloride 2- [N- (2,4,5-trimethoxybenzoyl) amino] -4 - [(2-di-n-propylaminoethyl) aminocarbonyl] -1,3-thiazole

IR (KBr) cm -1: 3400, 1663, 1611, 1550

1 H NMR (DMSO-d_ {6}) δ: 0.91 (6H, t), 1.65-1.80 (4H, m), 3.00-3.10 (4H, m), 3.20-3.25 (2H, m), 3.60-3.70 (2H, m), 3.79 (3H, s), 3.93 (3H, s), 4.08 (3H, s), 6.89 (1H, s), 7.50 (1H, s), 7.91 (1H, s), 8.69 (1H, t), 10.55 (2H, wide s), 11.32 (1H, s).

Example 79 Dihydrochloride 2- [N- (2,4,5-Trimethoxybenzoyl) amino] -4 - [(2-di-n-butylaminoethyl) aminocarbonyl] -1,3-thiazole

MS (FAB, m / z): 493 (MH +)

IR (KBr) cm -1: 3400, 1655, 1615, 1578, 1561

1 H NMR (CDCl 3) δ: 0.93-0.99 (6H, m), 1.33-1.47 (4H, m), 1.77-1.88 (4H, m), 3.11-3.15 (4H, m), 3.39-3.41 (2H, m), 3.92 (3H, s), 3.98 (2H, wide s), 3.99 (3H, s), 4.21 (3H, s), 6.58 (1H, s), 7.71 (1H, s), 8.06 (1H, s), 8.93 (1H, wide s), 11.61 (2H, wide s), 11.76 (1H, wide s).

Example 80 Hydrochloride 2- [N- (2,4,5-Trimethoxybenzoyl) amino] -4 - [(2-diisobutylaminoethyl) aminocarbonyl] -1,3-thiazole

MS (FAB, m / z): 493 (MH +)

IR (KBr) cm -1: 3650, 1559, 1541, 1509

1 H NMR (DMSO-d_ {6}) δ: 0.99-1.05 (12H, m), 2.09-2.19 (2H, m), 3.01-3.05 (4H, m), 3.31 (2H, wide s), 3.69-3.71 (2H, m), 3.79 (3H, s), 3.93 (3H, s), 4.07 (3H, s), 6.89 (1H, s), 7.50 (1H, s), 7.94 (1H, s), 8.78 (1H, s), 9.55 (1H, s), 11.31 (1H, s).

Example 81 2- [N- (2,4,5-Trimethoxybenzoyl) amino] -4 - [(2-dicyclohexylaminoethyl) aminocarbonyl] -1,3-thiazole

MS (FAB, m / z): 545 (MH +)

IR (KBr) cm -1: 3400, 1657, 1611, 1543, 1518

1 H NMR (CDCl 3) δ: 1.05-1.80 (20H, m), 2.57 (2H, broad s), 2.77-2.82 (2H, m), 3.36-3.43 (2H, m), 3.93 (3H, s), 3.99 (3H, s), 4.10 (3H, s), 6.59 (1H, s), 7.73 (1H, s), 7.73-7.77 (1H, m), 7.79 (1H, s), 11.06 (1H, s width).

Example 82 2- [N- (2,4,5-Trimethoxybenzoyl) amino] -4 - [[2- (N-ethyl-N-methylamino) ethyl] aminocarbonyl] -1,3-thiazole

MS (EI, m / z): 422 (M +)

IR (KBr) cm -1: 3318, 1650, 1609

1 H NMR (CDCl 3) δ: 1.11 (3H, t), 2.30 (3H, s), 2.52 (2H, c), 2.61 (2H, t), 3.54 (2H, c), 3.93 (3H, s), 3.99 (3H, s), 4.13 (3H, s), 6.59 (1H, s), 7.56 (1H, broad t), 7.75 (1H, s), 7.78 (1H, s), 11.05 (1H, s width).

Example 83 Dihydrochloride 2- [N- (2,4,5-trimethoxybenzoyl) amino] -4 - [[2- (N-isopropyl-N-n-propylamino) ethyl] aminocarbonyl] -1,3-thiazole

1 H NMR (CDCl 3) δ: 0.96 (3H, t), 1.02-1.10 (6H, m), 1.43-1.60 (2H, m), 1.58-1.79 (4H, m), 2.38-2.53 (2H, m), 2.59-2.71 (2H, m), 2.97-3.09 (1H, m), 3.41-3.55 (2H, m), 3.93 (3H, s), 3.99 (3H, s), 4.10 (3H, s), 6.59 (1H, s), 7.74 (1H, s), 7.79 (1H, s), 7.74-8.02 (1H, m), 11.42 (1H, s).

Example 84 Dihydrochloride 2- [N- (2,4,5-trimethoxybenzoyl) amino] -4 - [[2- (N-isopropyl-N-n-butylamino) ethyl] aminocarbonyl] -1,3-thiazole

1 H NMR (CDCl 3) δ: 0.91 (3H, t), 1.05 (6H, d), 1.33-1.47 (4H, m), 1.83-2.02 (2H, m), 2-45-2.51 (2H, m), 2.63-2.68 (2H, m), 3.01-3.06 (1H, m), 3.44-3.49 (2H, m), 3.93 (3H, s), 3.99 (3H, s), 4.16 (3H, s), 6.59 (1H, s), 7.74 (1H, s), 7.79 (1H, s), 7.72-7.79 (1H, m), 9.86-9.98 (2H, m), 11.07 (1H, s).

Example 85 Dihydrochloride 2- [N- (2,4,5-Trimethoxybenzoyl) amino] -4 - [(2-diisopropylaminoethyl) aminocarbonyl] -5-chloro-1,3-thiazole

1 H NMR (DMSO-d_ {6}) δ: 1.30-1.37 (12H, m), 3.10-3.28 (2H, m), 3.53-3.89 (4H, m), 3.78 (3H, s), 3.93 (3H, s), 4.07 (3H, s), 6.88 (1H, s), 7.46 (1H, s), 8.67-8.80 (1H, m), 9.76-9.94 (2H, m), 11.42 (1H, s).

Example 86 Dihydrochloride 2- [N- (2,4,5-Trimethoxybenzoyl) amino] -4 - [(2-diisopropylaminoethyl) aminocarbonyl] -5-methyl-1,3-thiazole

1 H NMR (DMSO-d_ {6}) δ: 1.29-1.36 (12H, m), 2.68 (3H, s), 3.16-3.24 (2H, m), 3.52-3.61 (4H, m), 3.78 (3H, s), 3.92 (3H, s), 4.08 (3H, s), 6.88 (1H, s), 7.50 (1H, s), 8.54-8.63 (1H, m), 9.58-9.70 (2H, m), 11.16 (1H, s).

Example 87 2- [N- (2,4,5-Trimethoxybenzoyl) amino] -4 - [[2- (N-methoxy-N-methylamino) ethyl] aminocarbonyl] -1,3-thiazole

MS (FAB, m / z): 425 (MH +)

IR (KBr) cm -1: 1657, 1608, 1537, 1263, 1024

1 H NMR (CDCl 3) δ: 2.65 (3H, s), 2.87 (2H, t), 3.60 (3H, s), 3.65 (2H, c), 3.93 (3H, s), 4.00 (3H, s), 4.12 (3H, s), 6.59 (1H, s), 7.59 (1H, t), 7.76 (1H, s), 7.78 (1H, s), 11.03 (1H, s).

Example 88 Dihydrochloride 2- [N- (2,4,5-trimethoxybenzoyl) amino] -4 - [[2- (N-2-methoxyethyl-N-isopropylamino) ethyl] aminocarbonyl] -1,3-thiazole

MS (FAB, m / z): 481 (MH +)

1 H NMR (DMSO-d_ {6}) δ: 1.28 (6H, d), 3.22-3.35 (4H, m), 3.29 (3H, s), 3.67-3.74 (5H, m), 3.78 (3H, s), 3.93 (3H, s), 4.08 (3H, s), 6.89 (1H, s), 7.50 (1H, s), 7.92 (1H, s), 8.72 (1H, t), 9.96 (2H, wide s), 11.32 (1H, s).

Example 89 Dimaleate of 2- [N- (2,4,5-trimethoxybenzoyl) amino] -4 - [[2- [N- (2-dimethylaminoethyl) -N-methylamino] ethyl] aminocarbonyl] -1,3-thiazole

IR (KBr) cm -1: 3322, 1655

1 H NMR (DMSO-d6) δ: 2.40 (3H, s), 2.76 (6H, s), 2.83-2.95 (2H, m), 3.15-3.20 (2H, m), 3.43-3.46 (4H, m), 3.50 (4H, broad s), 3.78 (3H, s), 3.93 (3H, s), 4.07 (3H, s), 6.12 (4H, s), 6.89 (1H, s), 7.50 (1H, s), 7.84 (1H, s), 8.29 (1H, t), 11.26 (1H, s).

Example 90 2- [N- (2,4,5-Trimethoxybenzoyl) amino] -4 - [[2- [N- (3,4-dimethoxybenzyl) -N-isopropylamino] ethyl] aminocarbonyl] -1,3-thiazole

IR (KBr) cm -1: 3339, 1671, 1611

1 H NMR (CDCl 3) δ: 1.08 (6H, d), 2.69 (2H, t), 2.95-3.05 (1H, m), 3.44 (2H, c), 3.59 (2H, s), 3.79 (3H, s), 3.81 (3H, s), 3.93 (3H, s), 3.99 (3H, s), 4.02 (3H, s), 6.57 (1H, s), 6.78 (1H, d), 6.92 (1H, dd), 6.98 (1H, d), 7.74 (1H, s), 7.74-7.79 (1H, m), 7.79 (1H, s), 11.09 (1H, s).

Example 91 Hydrochloride 2- [N- (2,4,5-trimethoxybenzoyl) amino] -4 - [[2- [N- (3,4-dimethoxyphenyl) ethyl] -N-isopropylamino] ethyl] aminocarbonyl] -1,3-thiazole

IR (KBr) cm -1: 3450, 1675, 1600, 1609

1 H NMR (DMSO-d6) δ: 1.32 (6H, t), 3.07 (2H, t), 3.11-3.40 (4H, m), 3.70-3.80 (4H, m), 3.71 (3H, s), 3.75 (3H, s), 3.79 (3H, s), 3.93 (3H, s), 4.08 (3H, s), 6.79-6.93 (3H, m), 7.51 (1H, s), 7.91 (1H, s), 8.77 (1H, t), 10.52 (1H, wide s), 11.34 (1H, s).

Example 92 2- [N- (2-Ethoxy-4,5-dimethoxybenzoyl) amino] -4 - [(2-dimethylaminoethyl) aminocarbonyl] -1,3-thiazole

IR (KBr) cm -1: 3314, 1661, 1611, 1545, 1514

1 H NMR (CDCl 3) δ: 1.69 (3H, t), 2.29 (6H, s), 2.53 (2H, t), 3.51 (2H, c), 3.93 (3H, s), 3.97 (3H, s), 4.34 (2H, c), 6.58 (1H, s), 7.70 (1H, s width), 7.74 (1H, s), 7.77 (1H, s), 11.37 (1H, s).

Example 93 2- [N- (4,5-Dimethoxy-2-isopropylbenzoyl) amino] -4 - [(2-dimethylaminoethyl) aminocarbonyl] -1,3-thiazole

IR (KBr) cm -1: 3308, 1673, 1661, 1613

1 H NMR (CDCl 3) δ: 1.56 (6H, d), 2.30 (6H, s), 2.53 (2H, t), 3.52 (2H, c), 3.93 (3H, s), 3.96 (3H, s), 4.75-4.85 (1H, m), 6.59 (1H, s), 7.71 (1H, wide s), 7.74 (1H, s), 7.75 (1H, s), 11.54 (1H, s).

Example 94 Fumarate of 2- [N- (4,5-Diethoxy-2-methoxybenzoyl) amino] -4 - [(2-diisopropylaminoethyl) aminocarbonyl] -1,3-thiazole

IR (KBr) cm -1: 3300, 2980, 2960, 2600, 2500, 1670, 1650, 1600

1 H NMR (DMSO-d6) δ: 1.11 (12H, d), 1.31 (3H, t), 1.38 (3H, t), 2.75-2.85 (2H, m), 3.18-3.35 (2H, m), 3.35-3.45 (2H, m), 3.80 (2H, broad s), 4.02 (2H, c), 4.04 (3H, s), 4.20 (2H, c), 6.59 (2H, s), 6.85 (1H, s), 7.49 (1H, s), 7.83 (1H, s), 8.37 (1H, s width), 11.29 (1H, s).

Example 95 2- [N- (2-Benzyloxy-4,5-dimethoxybenzoyl) amino] -4 - [(2-dimethylaminoethyl) aminocarbonyl] -1,3-thiazole

IR (KBr) cm -1: 3318, 1671, 1647, 1607

1 H NMR (CDCl 3) δ: 2.32 (6H, s), 2.54 (2H, t), 3.55 (2H, c), 3.93 (3H, s), 3.94 (3H, s), 5.33 (2H, s), 6.65 (1H, s), 7.25 (1H, wide s), 7.42-7.57 (5H, m), 7.72 (1H, s), 7.78 (1H, s), 11.19 (1H, s).

Example 96 Dihydrochloride 2- [N- (2-hydroxy-4,5-dimethoxybenzoyl) amino] -4 - [(2-isopropylaminoethyl) aminocarbonyl] -1,3-thiazole

MS (FAB, m / z): 409 (MH +)

IR (KBr) cm -1: 2976, 1647, 1560, 1269, 1213

1 H NMR (DMSO-d_ {6}) δ: 1.23 (6H, d), 3.07 (2H, s width), 3.33 (1H, td), 3.55-3.62 (2H, m), 3.77 (3H, s), 3.81 (3H, s), 6.89 (1H, s), 7.50 (1H, s), 7.90 (1H, s), 8.64-8.70 (3H, m), 11.80 (1H, s), 12.02 (2H, s width).

Example 97 Dihydrochloride 2- [N- (2-hydroxy-4,5-dimethoxybenzoyl) amino] -4 - [[2- (N-methyl-N-isopropylamino) ethyl] aminocarbo-nyl] -1,3-thiazole

MS (FAB, m / z): 423 (MH +)

IR (KBr) cm -1: 3010, 1662, 1551, 1292, 1213

1 H NMR (DMSO-d6) δ: 1.24 (6H, dd), 2.72 (3H, d), 3.07-3.14 (1H, m), 3.26-3.33 (1H, m), 3.58-3.65 (3H, m), 3.77 (3H, s), 3.81 (3H, s), 6.88 (1H, s), 7.50 (1H, s), 7.90 (1H, s), 8.71 (1H, t), 9.80 (1H, wide s), 11.79 (1H, s), 12.02 (2H, wide s).

Example 98 Dihydrochloride 2- [N- (2-hydroxy-4,5-dimethoxybenzoyl) amino] -4 - [[2- (N-ethyl-N-isopropylamino) ethyl] aminocarbonyl] -1,3-thiazole

MS (FAB, m / z): 437 (MH +)

IR (KBr) cm -1: 3010, 1660, 1551, 1520, 1292, 1161

1 H NMR (DMSO-d_ {6}) δ: 1.24-1.31 (9H, m), 3.10-3.35 (4H, m), 3.59-3.67 (3H, m), 3.77 (3H, s), 3.82 (3H, s), 6.84 (1H, s), 7.50 (1H, s), 7.90 (1H, s), 8.72 (1H, t), 9.56 (1H, s wide), 11.78 (1H, s), 12.00 (2H, wide s).

Example 99 Dihydrochloride 2- [N- (2-hydroxy-4,5-dimethoxybenzoyl) amino] -4 - [[2- (N-isopropyl-N-n-propylamino) ethyl] aminocarbonyl] -1,3-thiazole

MS (FAB, m / z): 451 (MH +)

IR (KBr) cm -1: 2980, 1672, 1641, 1600, 1265, 1213

1 H NMR (DMSO-d6) δ: 0.93 (3H, t), 1.27 (6H, d), 1.75 (2H, td), 2.98-3.16 (3H, m), 3.23-3.30 (1H, m), 3.62-3.66 (3H, m), 3.77 (3H, s), 3.81 (3H, s), 6.91 (1H, s), 7.49 (1H, s), 7.90 (1H, s), 8.76 (1H, t), 9.85 (1H, wide s), 11.79 (1H, s), 12.02 (2H, wide s).

Example 100 Maleate 2- [N- (4-hydroxy-2,5-dimethoxybenzoyl) amino] -4 - [(2-dimethylaminoethyl) aminocarbonyl] -1,3-thiazole

IR (KBr) cm -1: 3386, 3291, 1647, 1607, 1527

1 H NMR (DMSO-d_ {6}) δ: 2.83 (6H, s), 3.24-3.33 (4H, m), 3.50-3.61 (2H, m), 3.80 (3H, s), 3.97 (3H, s), 6.01 (2H, s), 6.74 (1H, s), 7.53 (1H, s), 7.87 (1H, s), 8.50-8.70 (1H, m), 10.30 (1H, s), 11.16 (1H, s).

Example 101 Hydrochloride 2- [N- (4-hydroxy-2,5-dimethoxybenzoyl) amino] -4 - [(2-isopropylaminoethyl) aminocarbonyl] -1,3-thiazole

IR (KBr) cm -1: 3308, 1674

1 H NMR (DMSO-d_ {6}) δ: 1.24 (6H, d), 3.00-3.13 (2H, m), 3.26-3.38 (1H, m), 3.56-3.66 (2H, m), 3.80 (3H, s), 3.90-4.10 (1H, m), 3.98 (3H, s), 6.78 (1H, s), 7.52 (1H, s), 7.89 (1H, s), 8.59 (1H, t), 8.70-8.95 (2H, width), 11.22 (1H, s).

Example 102 Hydrochloride 2- [N- (4-hydroxy-2,5-dimethoxybenzoyl) amino] -4 - [[2- (N-methyl-N-isopropylamino) ethyl] aminocarbonyl] -1,3-thiazole

IR (KBr) cm -1: 3200, 1684

1 H NMR (DMSO-d6) δ: 1.25 (6H, dd), 2.71 (3H, d), 3.01-3.16 (1H, m), 3.22-3.36 (1H, m), 3.51-3.78 (3H, m), 3.80 (3H, s), 3.98 (3H, s), 3.80-4.00 (1H, m), 6.78 (1H, s), 7.52 (1H, s), 7.89 (1H, s), 8.66 (1H, t), 10.20-10.30 (1H, width), 11.22 (1H, s).

Example 103 Hydrochloride 2- [N- (4-hydroxy-2,5-dimethoxybenzoyl) amino] -4 - [[2- (N-ethyl-N-isopropylamino) ethyl] aminocarbonyl] -1,3-thiazole

IR (KBr) cm -1: 3200, 1675

1 H NMR (DMSO-d_ {6}) δ: 1.22-1.31 (9H, m), 3.10-3.30 (4H, m), 3.60-3.75 (3H, m), 3.80 (3H, s), 3.98 (3H, s), 6.74 (1H, s), 7.52 (1H, s), 7.89 (1H, s), 8.60-8.70 (1H, m), 9.30-9.40 (1H, wide), 10.30 (1H, s), 11.18 (1H, s).

Example 104 Maleate 2- [N- (4-hydroxy-2,5-dimethoxybenzoyl) amino] -4 - [(2-diisopropylaminoethyl) aminocarbonyl] -1,3-thiazole

IR (KBr) cm -1: 3570, 3200, 1655, 1603, 1561

1 H NMR (DMSO-d_ {6}) δ: 1.29 (12H, d), 3.10-3.75 (8H, m), 3.80 (3H, s), 3.97 (3H, s), 6.03 (2H, s), 6.74 (1H, s), 7.52 (1H, s), 7.89 (1H, s), 8.56 (1H, s width), 10.32 (1H, s), 11.17 (1H, s).

Example 105 Dihydrochloride 2- [N- (4-hydroxy-2,5-dimethoxybenzoyl) amino] -4 - [[2- (N-isopropyl-N-n-propylamino) ethyl] aminocarbonyl] -1,3-thiazole

IR (KBr) cm -1: 3400, 3200, 1686, 1665, 1617, 1553

1 H NMR (DMSO-d6) δ: 0.93 (3H, t), 1.27 (3H, d), 1.28 (3H, d), 1.73-1.82 (2H, m), 3.00-3.17 (4H, m), 3.20-3.35 (1H, m), 3.57-3.78 (2H, m), 3.80 (3H, s), 3.98 (3H, s), 6.00-6.30 (2H, width), 6.79 (1H, s), 7.52 (1H, s), 7.89 (1H, s), 8.70 (1H, t), 10.20 (1H, wide s), 11.22 (1H, s).

Example 106 Maleate 2- [N- (5-hydroxy-2,4-dimethoxybenzoyl) amino] -4 - [(2-diisopropylaminoethyl) aminocarbonyl] -1,3-thiazole

IR (KBr) cm -1: 3650, 3200, 1663, 1541

1 H NMR (DMSO-d_ {6}) δ: 1.30 (12H, d), 3.19 (2H, s width), 3.33 (2H, wide s), 3.56 (2H, wide s), 3.68 (2H, wide s), 3.92 (3H, s), 4.04 (3H, s), 6.02 (2H, s), 6.84 (1H, s), 7.42 (1H, s), 7.88 (1H, s), 8.55 (1H, wide s), 9.15 (1H, s), 11.22 (1H, s).

Example 107 Hydrochloride 2- [N- (4,5-dihydroxy-2-methoxybenzoyl) amino] -4 - [(2-diisopropylaminoethyl) aminocarbonyl] -1,3-thiazole

IR (KBr) cm -1: 3400, 1655, 1607

1 H NMR (DMSO-d6) δ: 1.31 (6H, d), 1.34 (6H, d), 3.15-3.18 (2H, m), 3.60-3.75 (4H, m), 3.96 (3H, s), 6.69 (1H, s), 7.44 (1H, s), 7.85 (1H, d), 8.66 (1H, t), 9.20 (1H, s), 9.70 (1H, wide s), 10.10 (1H, s), 11.18 (1H,  s).

Example 108 Dihydrochloride 2- [N- (2,4-dihydroxy-5-methoxybenzoyl) amino] -4 - [(2-diisopropylaminoethyl) aminocarbonyl] -1,3-thiazole

1 H NMR (CDCl 3) δ: 1.46 (12H, d), 1.84-1.89 (2H, m), 3.21-3.27 (2H, m), 3.65-3.78 (2H, m), 3.92-3.98 (2H, m), 3.94 (3H, s), 6.58 (1H, s), 7.54 (1H, s), 7.80 (1H, s), 8.97-9.05 (1H, m), 10.79-10.92 (2H, m), 11.45 (1H, s).

Example 109 Hydrochloride 2- [N- (2-Acetyloxy-4,5-dimethoxybenzoyl) amino] -4 - [(2-diisopropylaminoethyl) aminocarbonyl] -1,3-thiazole

In 10.5 ml of acetic anhydride, they were suspended 3.7 g of hydrochloride 2- [N- (4,5-dimethoxy-2-hydroxybenzoyl) amino] -4 - [(2-diisopropylaminoethyl) aminocarbonyl] -1,3-thiazole obtained in Example 38, followed by stirring at 90 ° C for 3 hours. After allowing the reaction mixture to cool, it 100 ml of toluene was added thereto. The precipitated crystals of this mode was collected by filtration, followed by drying, with that 3.33 g of the title compound were obtained. Performance: 91%

1 H NMR (DMSO-d6) δ: 1.31 (6H, d), 1.35 (6H, d), 3.19 (2H, broad s), 3.59-3.69 (4H, m), 3.83 (3H, s), 3.87 (3H, s), 6.91 (1H, s), 7.42 (1H, s), 7.91 (1H, s), 8.44 (1H, t), 10.07 (1H, broad s), 12.49 (1H, s).

Example 110 Dihydrochloride 2- [N- (2-Chloro-4,5-dimethoxybenzoyl) amino] -4 - [(2-dimethylaminoethyl) aminocarbonyl] -1,3-thiazole

1 H NMR (CDCl 3) δ: 2.27 (6H, s), 2.52-2.57 (2H, m), 3.51-3.55 (2H, m), 3.94 (3H, s), 3.96 (3H, s), 6.93 (1H, s), 7.53 (1H, s), 7.55 (1H, s), 7.79 (1H, s), 10.50 (3H, s width).

Example 111 Dihydrochloride 2- [N- (2-Chloro-4,5-dimethoxybenzoyl) amino] -4 - [(2-diisopropylaminoethyl) aminocarbonyl] -1,3-thiazole

1 H NMR (CDCl 3) δ: 1.44-1.53 (12H, m), 3.39-3.50 (2H, m), 3.48-3.82 (4H, m), 3.71-3.93 (2H, m), 3.95 (3H, s), 4.02 (3H, s), 6.90-7.02 (1H, m), 6.96 (1H, s), 7.57 (1H, s), 8.38 (1H, s), 9.60-9.75 (1H, m), 10.10-10.37 (1H, m), 13.46-13.68 (1H, m).

Example 112 Dihydrochloride 2- [N- (2-Bromo-4,5-dimethoxybenzoyl) amino] -4 - [(2-diisopropylaminoethyl) aminocarbonyl] -1,3-thiazole

IR (KBr) cm -1: 3250, 1690, 1597, 1559

1 H NMR (DMSO-d6) δ: 1.31 (6H, d), 1.35 (6H, d), 3.17 (2H, broad s), 3.50-3.70 (4H, m), 3.81 (3H, s), 3.85 (3H, s), 7.24 (1H, s), 7.26 (1H, s), 7.95 (1H, s), 8.44 (1H, t), 10.19 (2H, wide s), 12.72 (1H, wide s).

Example 113 2- [N- (4,5-Dimethoxy-2-nitrobenzoyl) amino] -4 - [(2-diisopropylaminoethyl) aminocarbonyl] -1,3-thiazole

MS (FAB, m / z): 480 (MH +)

IR (KBr) cm -1: 1549, 1523, 1294, 1059

1 H NMR (CDCl 3) δ: 0.98 (12H, d), 2.62 (2H, t), 2.99 (2H, td), 3.29 (2H, c), 3.97 (3H, s), 4.02 (3H, s), 6.99 (1H, s), 7.36 (1H, wide s), 7.63 (1H, s), 7.74 (1H, s).

Example 114 Dihydrochloride 2- [N- (2-amino-4,5-dimethoxybenzoyl) amino] -4 - [(2-diisopropylaminoethyl) aminocarbonyl] -1,3-thiazole

1 H NMR (DMSO-d_ {6}) δ: 1.30-1.37 (12H, m), 3.18 (2H, wide s), 3.60-3.69 (4H, m), 3.80 (3H, s), 3.81 (3H, s), 4.25-5.75 (4H, m), 6.82 (1H, s), 7.52 (1H, s), 7.93 (1H, s), 8.50 (1H, t), 10.15 (1H, s).

Example 115 Maleate 2- [N- (4,5-dimethoxy-2-fluorobenzoyl) amino] -4 - [(2-diisopropylaminoethyl) aminocarbonyl] -1,3-thiazole

MS (FAB, m / z): 453 (MH +)

IR (KBr) cm -1: 1662, 1545, 1354, 1273

1 H NMR (DMSO-d_ {6}) δ: 1.29 (12H, d), 3.19 (2H, s width), 3.55 (2H, wide s), 3.67 (2H, wide s), 3.82 (3H, s), 3.86 (3H, s), 6.02 (2H, s), 7.07 (1H, d), 7.31 (1H, d), 7.92 (1H, s), 8.39 (1H, wide s), 8.56 (2H, wide s), 12.11 (1H, s).

Example 116 Fumarate of 2- [N- (4-amino-2,5-dimethoxybenzoyl) amino] -4 - [(2-diisopropylaminoethyl) aminocarbonyl] -1,3-thiazole

1 H NMR (DMSO-d_ {6}) δ: 1.07-1.12 (12H, m), 2.72-2.76 (2H, m), 3.17-3.22 (2H, m), 3.31-3.42 (2H, m), 3.80 (3H, s), 3.95 (2H, s), 4.01 (3H, s), 5.95 (1H, s), 6.59 (2H, s), 6.78 (1H, s), 7.39 (1H, d), 7.77 (1H, d), 8.31-8.33 (1H, m), 8.81 (1H, s), 11.14 (1H, s).

Example 117 2- [N- (2,5-Dimethoxy-4-formylaminobenzoyl) amino] -4 - [(2-diisopropylaminoethyl) aminocarbonyl] -1,3-thiazole

1 H NMR (CDCl 3) δ: 1.08 (12H, d), 1.61 (1H, s), 2.67-2.72 (2H, m), 3.05-3.12 (2H, m), 3.40-3.43 (2H, m), 3.95 (3H, s), 4.10 (3H, s), 7.75 (1H, s), 7.82 (1H, s), 8.08 (1H, s), 8.38 (1H, s), 8.55 (1H, s), 11.18 (1H, s).

Example 118 Hydrochloride 2- [N- (4-acetylamino-2,5-dimethoxybenzoyl) amino] -4 - [(2-diisopropylaminoethyl) aminocarbonyl] -1,3-thiazole

1 H NMR (DMSO-d_ {6}) δ: 1.33-1.37 (12H, m), 2.18 (3H, s), 3.15-3.17 (2H, m), 3.56-3.70 (4H, m), 3.89 (3H, s), 3.98 (3H, s), 4.90-5.20 (2H, m), 7.55 (1H, s), 7.91 (1H, s), 8.22 (1H, s), 8.65-8.73 (1H, m), 9.50 (1H, s), 10.03 (1H, s), 11.42 (1H, s).

Example 119 Hydrochloride 2- [N- (2,5-dimethoxy-4-nitrobenzoyl) amino] -4 - [(2-diisopropylaminoethyl) aminocarbonyl] -1,3-thiazole

1 H NMR (CDCl 3) δ: 1.42-1.54 (12H, m), 1.57 (2H, s), 3.20-3.22 (2H, m), 3.61-3.64 (2H, m), 3.92-4.01 (2H, m), 4.01 (3H, s), 4.23 (3H, s), 7.55 (1H, s), 7.86 (1H, s), 8.06 (1H, s), 9.10-9.20 (1H, m), 11.20-11.30 (1H, m), 11.46 (1H, s).

Example 120 Hydrochloride 2- [N- (4-Bromo-2,5-dimethoxybenzoyl) amino] -4 - [(2-diisopropylaminoethyl) aminocarbonyl] -1,3-thiazole

1 H NMR (CDCl 3) δ: 1.43 (6H, d), 1.53 (6H, d), 3.15-3.30 (2H, m), 3.50 -3.65 (2H, m), 3.90-4.05 (2H, m), 3.94 (3H, s), 4.17 (3H, s), 7.29 (1H, s), 7.81 (1H, s), 7.82 (1H, s), 9.07 (1H, wide s), 11.25 (1H, wide s), 11.40
(1H, s).

Example 121 Hydrochloride 2- [N- (4-Bromo-2-hydroxy-5-methoxybenzoyl) amino] -4 - [(2-diisopropylaminoethyl) aminocarbonyl] -1,3-thiazole

1 H NMR (CDCl 3 + 5% -CD 3 OD) δ: 1.40-1.50 (12H, m), 3.28 (2H, t), 3.37-3.75 (2H, m), 3.88 (2H, t), 3.95 (3H, s), 7.37 (1H, s), 7.66 (1H, s), 7.84 (1H, s).

Example 122 Hydrochloride 2- [N- (4,5-dichloro-2-methoxybenzoyl) amino] -4 - [(2-diisopropylaminoethyl) aminocarbonyl] -1,3-thiazole

1 H NMR (CDCl 3) δ: 1.43 (6H, d), 1.52 (6H, d), 3.20 (2H, broad s), 3.57-3.64 (2H, m), 3.90-4.00 (2H, m), 4.21 (3H, s), 7.17 (1H, s), 7.82 (1H, s), 8.35 (1H, s), 9.10 (1H, wide s), 11.21 (1H, s).

Example 123 Hydrochloride 2- [N- (4,5-dichloro-2-hydroxybenzoyl) amino] -4 - [(2-diisopropylaminoethyl) aminocarbonyl] -1,3-thiazole

1 H NMR (CDCl 3) δ: 1.45 (6H, d), 1.53 (6H, d), 3.32 (2H, broad s), 3.66 (2H, s wide), 7.30 (1H, s), 7.82 (1H, s), 8.22 (1H, s), 8.97 (1H, s wide), 10.49 (1H, wide s).

Example 124 Maleate 2- [N- (4-amino-5-chloro-2-methoxybenzoyl) amino] -4 - [(2-dimethylaminoethyl) aminocarbonyl] -1,3-thiazole

IR (KBr) cm -1: 3400, 3350, 3220, 1655, 1601

1 H NMR (CDCl 3, was measured a compound in the form of a free base) δ: 2.30 (6H, s), 2.53 (2H, t), 3.53 (2H, c), 4.07 (3H, s), 4.59 (2H, wide s), 6.35 (1H, s), 7.73 (1H, s), 7.45 (1H, wide s), 8.19 (1H, s), 10.79 (1H, s).

Example 125 Dihydrochloride 2- [N- (4-amino-5-chloro-2-methoxybenzoyl) amino] -4 - [(2-diisopropylaminoethyl) aminocarbonyl] -1,3-thiazole

1 H NMR (DMSO-d_ {6}) δ: 1.32-1.37 (12H, m), 3.10-3.25 (2H, m), 3.60-3.75 (4H, m), 3.98 (3H, s), 4.77 (3H, wide s), 6.61 (1H, s), 7.80 (1H, s), 7.84 (1H, s), 8.70 (1H, t), 10.20 (1H, s), 11.03 (1H, s).

Example 126 Hydrochloride 2- [N- (4-acetylamino-5-chloro-2-methoxybenzoyl) amino] -4 - [(2-diisopropylaminoethyl) aminocarbonyl] -1,3-thiazole

1 H NMR (DMSO-d6) δ: 1.32 (6H, d), 1.35 (6H, d), 2.19 (3H, s), 3.17 (2H, wide s), 3.29 (2H, wide s), 3.50-3.75 (2H, m), 3.96 (3H, s), 7.84 (1H, s), 7.91 (1H, s), 7.92 (1H, s), 8.61 (1H, wide s), 9.65 (1H, s), 10.01 (1H, s width), 11.62 (1H, s).

Example 127 2- [N- (2,4,5-Trimethoxybenzoyl) amino] -4 - [(2 - [(2-thiazolidiniden) imino] ethyl] aminocarbonyl] -1,3-thiazole

MS (FAB, m / z): 466 (MH +)

IR (KBr) cm -1: 3432, 3289, 1669, 1609, 1545, 1516

1 H NMR (CDCl 3) δ: 3.34-3.39 (2H, m), 3.57-3.61 (2H, m), 3.64-3.76 (2H, m), 3.89 (3H, s), 3.92-4.07 (5H, m), 4.15 (3H, s), 6.60 (1H, s), 7.76-7.81 (3H, m).

Example 128 2- [N- (2,4,5-Trimethoxybenzoyl) amino] -4 - [[2 - [(1-imidazolyl) ethyl] aminocarbonyl] -1,3-thiazole

MS (FAB, m / z): 432 (MH +)

IR (KBr) cm -1: 3537, 3424, 3308, 1653, 1611, 1541, 1518

1 H NMR (CDCl 3) δ: 3.73-3.79 (2H, m), 3.92 (3H, s), 3.99 (3H, s), 4.13 (3H, s), 4.21-4.25 (2H, m), 6.59 (1H, s), 6.98-6.99 (1H, m), 7.31 (1H, wide s), 7.53 (1H, s), 7.77-7.79 (2H, m), 11.01 (1H, s).

Example 129 2- [N- (4-Amino-2-hydroxy-5-methoxybenzoyl) amino] -4 - [(2-diisopropylaminoethyl) aminocarbonyl] -1,3-thiazole

1 H NMR (DMSO-d_ {6}) δ: 0.91-1.30 (2H, m), 2.48-2.51 (2H, m), 2.55-2.82 (2H, m), 2.98-3.48 (4H, m), 3.76 (3H, s), 5.74 (1H, s), 6.57 (1H, s), 7.33 (1H, s), 7.66-7.69 (1H, m), 8.03-8.50 (1H, m), 8.58-8.61 (1H, m).

Example 130 Dihydrochloride 2- [N- (4-formylamino-2-hydroxy-5-methoxybenzoyl) amino] -4 - [(2-diisopropylaminoethyl) aminocarbo-nyl] -1,3-thiazole

1 H NMR (DMSO-d_ {6}) δ: 1.25-1.36 (12H, m), 3.09-3.22 (2H, m), 3.41-3.56 (2H, m), 3.56 (1H, s), 3.51-3.77 (2H, m), 3.88 (3H, s), 7.57 (1H, s), 7.89 (1H, s), 8.22 (1H, s), 8.38 (1H, s), 8.60-8.72 (1H, m), 9.37-9.51 (1H, m), 10.02 (1H, s).

Example 131 Dihydrochloride 2- [N- (2-Methoxy-4-methyl-5-nitrobenzoyl) amino] -4 - [(2-diisopropylaminoethyl) aminocarbonyl] -1,3-thiazole

1 H NMR (DMSO-d_ {6}) δ: 1.30-1.36 (12H, m), 2.67 (2H, s), 3.17 (2H, s), 3.57 (3H, s), 3.55-3.71 (2H, m), 4.05 (3H, s), 7.37 (1H, s), 7.94 (1H, s), 8.42 (1H, s), 8.50-8.61 (1H, m), 9.76-9.89 (1H, m), 12.03 (1H, s).

Example 132 Hydrochloride 2- [N- (2,4-dimethoxy-5-nitrobenzoyl) amino] -4 - [(2-diisopropylaminoethyl) aminocarbonyl] -1,3-thiazole

1 H NMR (DMSO-d_ {6}) δ: 1.30-1.36 (12H, m), 3.14-3.22 (2H, m), 3.40-3.71 (4H, m), 4.09 (3H, s), 4.13 (3H, s), 7.00 (1H, s), 7.92 (1H, s), 8.42 (1H, s), 8.55-8.64 (1H, m), 9.79-9.88 (1H, m), 11.76 (1H, s).

Example 133 Dihydrochloride 2- [N- (5-amino-2,4-dimethoxybenzoyl) amino] -4 - [(2-diisopropylaminoethyl) aminocarbonyl] -1,3-thiazole

1 H NMR (DMSO-d_ {6}) δ: 1.30-1.36 (12H, m), 3.16 (2H, s), 3.29-3.42 (4H, m), 3.52-3.73 (2H, m), 4.05 (3H, s), 4.11 (3H, s), 7.01 (1H, s), 7.91 (1H, s), 7.97 (1H, s), 8.62-8.71 (1H, m), 9.77-9.89 (2H, m), 11.43 (1H, s).

Example 134 Hydrochloride 2- [N- (5-formylamino-2,4-dimethoxybenzoyl) amino] -4 - [(2-diisopropylaminoethyl) aminocarbonyl] -1,3-thiazole

1 H NMR (DMSO-d_ {6}) δ: 1.30-1.36 (12H, m), 3.10-3.23 (2H, m), 3.54-3.75 (4H, m), 4.01 (3H, s), 4.08 (3H, s), 6.92 (1H, s), 7.89 (1H, s), 8.28 (1H, s), 8.64-8.68 (1H, m), 8.72 (1H, s), 9.70 (1H, s), 9.69-9.80 (1H, m), 11.35 (1H, s).

Example 135 2- [N- (5-Acetylamino-2,4-dimethoxybenzoyl) amino] -4 - [(2-diisopropylaminoethyl) aminocarbonyl] -1,3-thiazole

1 H NMR (CDCl 3) δ: 1.02-1.14 (12H, m), 2.19 (3H, s), 2.62-2.78 (2H, m), 3.01-3.18 (2H, m), 3.37-3.49 (2H, m), 3.98 (3H, s), 4.09 (3H, s), 6.54 (1H, s), 7.40 (1H, s), 7.61-7.72 (2H, m), 9.04 (1H, s), 10.89 (1H, s).

Example 136 Hydrochloride 2- [N- (4-Methoxy-3-nitrobenzoyl) amino] -4 - [(2-diisopropylaminoethyl) aminocarbonyl] -1,3-thiazole

1 H NMR (CDCl 3) δ: 1.30-1.36 (12H, m), 3.19 (2H, wide s), 3.54 (1H, d), 3.60-3.70 (4H, m), 4.04 (3H, s), 4.30 (1H, wide s), 7.92 (1H, s), 8.33-8.37 (1H, m), 8.47 (1H, wide s), 8.67-8.71 (1H, m), 9.91 (1H, s width).

Example 137 Dihydrochloride 2- [N- (3-amino-4-methoxybenzoyl) amino] -4 - [(2-diisopropylaminoethyl) aminocarbonyl] -1,3-thiazole

1 H NMR (CDCl 3) δ: 1.30-1.36 (12H, m), 3.19 (2H, wide s), 3.60-3.75 (4H, m), 3.94 (3H, s), 4.70 (3H, wide s), 7.17 (1H, d), 7.76 (1H, s), 7.86 (1H, d), 7.91 (1H, s), 8.41 (1H, t), 9.94 (1H, wide s), 12.60 (1H, s).

Example 138 2- [N- (3-Formylamino-4-methoxybenzoyl) amino] -4 - [(2-diisopropylaminoethyl) aminocarbonyl] -1,3-thiazole

1 H NMR (DMSO-d_ {6}) δ: 0.98-1.05 (12H, m), 2.49-2.51 (2H, m), 2.99 (2H, wide s), 3.20-3.40 (2H, m), 3.95 (3H, s), 7.21 (1H, d), 7.75 (1H, s), 7.78 (1H, s), 7.91 (1H, dd), 8.35 (1H, d), 8.85 (1H, d), 9.81 (1H, s), 12.52 (1H, wide s).

Example 139 Hydrochloride 2- [N- (3-Acetylamino-4-methoxybenzoyl) amino] -4 - [(2-diisopropylaminoethyl) aminocarbonyl] -1,3-thiazole

1 H NMR (DMSO-d_ {6}) δ: 1.30-1.36 (12H, m), 2.12 (3H, s), 3.17 (2H, wide s), 3.60-3.75 (4H, m), 3.93 (3H, s), 7.21 (1H, d), 7.89-7.93 (1H, m), 7.90 (1H, s), 8.41 (1H, t), 8.66 (1H, s), 9.31 (1H, s), 9.74 (1H, wide s), 12.60 (1H, s).

Example 140 Hydrochloride 2- [N- (3-Methoxy-4-nitrobenzoyl) amino] -4 - [(2-diisopropylaminoethyl) aminocarbonyl] -1,3-thiazole

1 H NMR (DMSO-d_ {6}) δ: 1.32 (12H, broad s), 3.19 (2H, wide s), 3.64 (4H, wide s), 4.04 (3H, s), 7.72 (1H, d), 7.98-8.05 (2H, m), 8.40 (1H, s), 9.70 (1H, s wide), 13.15 (2H, wide s).

Example 141 Dihydrochloride 2- [N- (4-amino-3-methoxybenzoyl) amino] -4 - [(2-diisopropylaminoethyl) aminocarbonyl] -1,3-thiazole

1 H NMR (DMSO-d_ {6}) δ: 1.30-1.37 (12H, m), 3.17 (2H, wide s), 3.60-3.90 (4H, m), 3.90 (3H, s), 5.63 (3H, wide s), 6.91 (1H, d), 7.61 (1H, d), 7.67 (1H, s), 7.89 (1H, s), 8.44 (1H, wide s), 10.15 (1H, wide s), 12.40 (1H, wide s).

Example 142 Fumarate of 2- [N- (4-formylamino-3-methoxybenzoyl) amino] -4 - [(2-diisopropylaminoethyl) aminocarbonyl] -1,3-thiazole

1 H NMR (DMSO-d_ {6}) δ: 1.01-1.08 (12H, m), 2.61 (2H, t), 3.00-3.20 (2H, m), 3.29 (2H, c), 3.40 (2H, wide s), 3.97 (3H, s), 6.58 (1H, s), 7.74 (1H, d), 7.80 (1H, d), 7.82 (1H, s), 7.95 (1H, t), 8.37 (1H, d), 8.38 (1H, s), 9.98 (1H, s).

Example 143 Hydrochloride 2- [N- (4-acetylamino-3-methoxybenzoyl) amino] -4 - [(2-diisopropylaminoethyl) aminocarbonyl] -1,3-thiazole

1 H NMR (DMSO-d_ {6}) δ: 1.30-1.37 (12H, m), 2.15 (3H, s), 3.19 (2H, wide s), 3.47 (1H, wide s), 3.55-3.70 (4H, m), 3.96 (3H, s), 7.58 (1H, d), 7.69 (1H, d), 7.86 (1H, s), 8.24 (1H, d), 8.43 (1H, t), 9.37 (1H, s), 9.96 (1H, wide s).

Example 144 2- [N- (4-Amino-2-methoxybenzoyl) amino] -4 - [(2-diisopropylaminoethyl) aminocarbonyl] -1,3-thiazole

1 H NMR (CDCl 3) δ: 1.07 (12H, d), 2.67-2.71 (2H, m), 3.03-3.13 (2H, m), 3.37-3.44 (2H, m), 4.04 (3H, s), 4.21 (2H, s), 6.24-6.26 (1H, m), 6.38-6.42 (1H, m), 7.67-7.76 (1H, m), 7.69 (1H, s), 8.07-8.11 (1H, m), 10.90 (1H, s).

Example 145 2- [N- (4-Formylamino-2-methoxybenzoyl) amino] -4 - [(2-diisopropylaminoethyl) aminocarbonyl] -1,3-thiazole

1 H NMR (CDCl 3) δ: 1.08 (12H, d), 2.68-2.73 (2H, m), 3.03-3.14 (2H, m), 3.36-3.45 (2H, m), 4.13 (3H, s), 6.86-6.90 (1H, m), 7.69-7.74 (3H, m), 8.01 (1H, s), 8.24-8.29 (1H, m), 8.48 (1H, s), 11.02 (1H, s).

Example 146 Dihydrochloride 2- [N- (4-acetylamino-2-methoxybenzoyl) amino] -4 - [(2-diisopropylaminoethyl) aminocarbonyl] -1,3-thiazole

1 H NMR (DMSO-d_ {6}) δ: 1.24-1.46 (12H, m), 2.11 (3H, s), 3.17 (2H, s), 3.57-4.03 (6H, m), 3.99 (3H, s), 7.29-7.33 (1H, m), 7.68 (1H, s), 7.87-7.90 (2H, m), 8.60-8.65 (1H, m), 9.67 (2H, s), 10.45 (1H, s), 11.36 (1H, s).

Example 147 2- [N- (3,4-Dimethoxybenzoyl) amino] -4- [1- (4-dimethyl-amino) piperidinyl] carbonyl] -1,3-thiazole

MS (FAB, m / z): 419 (MH +)

IR (KBr) cm -1: 1655, 1601, 1549, 1516, 1269

1 H NMR (CDCl 3) δ: 1.41-1.56 (2H, m), 1.75-1.95 (2H, m), 2.30 (6H, s), 2.38-2.47 (1H, m), 2.60-3.15 (2H, m), 3.96 (3H, s), 3.97 (3H, s), 4.25-4.70 (2H, m), 6.96 (1H, d), 7.43 (1H, s), 7.48-7.56 (2H, m), 9.60 (1H, wide s).

Example 148 2- [N- (3,4-Dimethoxybenzoyl) amino] -4- [1- (4-methyl-piperazinyl)] carbonyl] -1,3-thiazole

IR (KBr) cm -1: 3084, 1655, 1601, 1547

1 H NMR (CDCl 3) δ: 2.30 (3H, s), 2.40 (4H, wide s), 3.74 (4H, wide s), 3.95 (3H, s), 3.96 (3H, s), 6.94 (1H, d), 7.47 (1H, s), 7.51 (1H, dd), 7.56 (1H, d), 10.00 (1H, wide s).

Example 149 Maleate 2- [N- (2,4,5-Trimethoxybenzoyl) amino] -4 - [[(2-dimethylamino-1-methyl) ethyl] aminocarbonyl] -1,3-thiazole

MS (EI, m / z): 422 (M +)

IR (KBr) cm -1: 3289, 1711, 1665, 1610

1 H NMR (DMSO-d6) δ: 1.22 (3H, d), 2.81 (6H, s),  3.08-3.40 (2H, m), 3.79 (3H, s), 3.93 (3H, s), 4.08 (3H, s), 4.44-4.48 (1H, m), 6.01 (2H, s), 6.88 (1H, s), 7.51 (1H, s), 7.89 (1H, s), 8.33 (1H, d), 8.70-9.50 (1H, width), 11.24 (1H, s).

Example 150 2- [N- (2,4,5-Trimethoxybenzoyl) amino] -4 - [(4-dimethylaminophenyl) aminocarbonyl] -1,3-thiazole

MS (FAB, m / z): 456 (MH +)

IR (KBr) cm -1: 3335, 1659, 1640, 1609, 1516

1 H NMR (CDCl 3) δ: 2.95 (6H, s), 3.93 (3H, s), 4.00 (3H, s), 4.17 (3H, s), 6.61 (1H, s), 6.76 (2H, d), 7.58 (2H, d), 7.83 (1H, s), 7.84 (1H, s), 8.87 (1H, wide s), 11.06 (1H, wide s).

Example 151 2- [N- (2,4,5-Trimethoxybenzoyl) amino] -4 - [[4- (1-methylpiperidinyl) aminocarbonyl] -1,3-thiazole

MS (FAB, m / z): 435 (MH +)

IR (KBr) cm -1: 3519, 3357, 1655, 1611, 1538

1 H NMR (CDCl 3) δ: 1.61-1.75 (2H, m), 2.03-2.24 (5H, m), 2.34 (3H, s), 2.87-2.92 (2H, m), 3.93 (3H, s), 3.99 (3H, s), 4.15 (3H, s), 6.60 (1H, s), 7.08 (1H, broad d), 7.76 (1H, s), 7.78 (1H, s), 11.03 (1H, wide s).

Example 152 Dihydrochloride 2- [N- (2,4,5-Trimethoxybenzoyl) amino] -4 - [[[2- (1-methylpiperidinyl)] methyl] aminocarbonyl] -1,3-thiazole

MS (FAB, m / z): 449 (MH +)

IR (KBr) cm -1: 3185, 1665, 1607, 1551

1 H NMR (DMSO-d_ {6}) δ: 1.79-1.98 (6H, m), 2.80-2.83 (3H, m), 3.05-3.55 (4H, m), 3.79 (3H, s), 3.93 (3H, s), 4.10 (3H, d), 4.42 (1H, wide s), 6.88 (1H, s), 7.50 (1H, d), 7.89 (1H, d), 8.39 (0.5H, d), 8.69 (0.5H, d), 10.98 (0.5H, wide s), 11.30 (0.5H, wide s), 11.38 (2H, wide s).

Example 153 Hydrochloride 2- [N- (4,5-dimethoxy-2-hydroxybenzoyl) amino] -4 - [(2-diisopropylaminoethyl) oxycarbonyl] -1,3-thiazole

IR (KBr) cm -1: 3185, 1665, 1607, 1551

1 H NMR (DMSO-d_ {6}) δ: 1.23-1.42 (12H, m), 3.28-3.48 (2H, m), 3.65-3.71 (2H, m), 3.78 (3H, s), 3.82 (3H, s), 4.52-4.63 (2H, m), 6.70 (1H, s), 7.60 (1H, s), 8.18 (1H, s), 9.84 (1H, s), 11.91-11.98 (1H, m), 12.28 (1H, s).

Example 154 Maleate 2- [N- (2-Methoxy-3,4-methylidenedioxybenzoyl) amino] -4 - [(2-diisopropylaminoethyl) aminocarbonyl] -1,3-thiazole

IR (KBr) cm -1: 3250, 1653, 1541

1 H NMR (DMSO-d_ {6}) δ: 1.30 (12H, d), 3.10-3.25 (2H, m), 3.50-3.72 (4H, m), 3.99 (3H, s), 6.03 (2H, s), 6.13 (2H, s), 7.09 (1H, s), 7.41 (1H, s), 7.89 (1H, s), 8.52 (1H, wide s), 8.60 (2H, wide s), 11.34 (1H, s).

Example 155 Trihydrochloride 2- [N- [2- (2-dimethylaminoethylamino) -4,5-dimethoxybenzoyl) amino] -4 - [(2-dimethylaminoethyl) aminocarbonyl] -1,3-thiazole

IR (KBr) cm -1: 3030, 1655, 1560, 1538

1 H NMR (DMSO-d_ {6}) δ: 2.70-2.90 (12H, m), 3.20-3.30 (4H, m), 3.60-3.75 (4H, m), 3.78 (3H, s), 3.91 (3H, s), 6.10 (3H, wide s), 6.46 (1H, s), 7.53 (1H, s), 7.93 (1H, s), 8.32 (1H, t), 10.40 (1H, wide s), 10.90 (1H, wide s).

Example 156 Hydrochloride 2- [N- (3-nitrobenzoyl) amino] -4 - [(2-diisopropylaminoethyl) aminocarbonyl] -1,3-thiazole

1 H NMR (DMSO-d6) δ: 1.31 (6H, d), 1.34 (6H, d), 3.20 (2H, broad s), 3.60-3.68 (4H, m), 7.88 (1H, dd), 7.99 (1H, s), 8.48-8.52 (2H, m), 8.94 (1H, dd), 9.63 (1H, s), 13.21 (1H, s).

Example 157 2- [N- (3-Aminobenzoyl) amino] -4 - [(2-diisopropylaminoethyl) aminocarbonyl] -1,3-thiazole

1 H NMR (DMSO-d_ {6}) δ: 0.98 (12H, d), 2.51 (2H, s wide), 2.99 (2H, wide s), 3.20-3.40 (2H, m), 5.37 (2H, s), 6.78-6.82 (1H, m), 7.14-7.22 (3H, m), 7.78 (1H, s), 7.82 (1H, wide s), 12.43 (1H, s).

Example 158 2- [N- (3-Formylaminobenzoyl) amino] -4 - [(2-diisopropylaminoethyl) aminocarbonyl] -1,3-thiazole

1 H NMR (DMSO-d_ {6}) δ: 0.99 (12H, d), 2.56 (2H, s wide), 3.00 (2H, wide s), 3.15-3.35 (2H, m), 7.50 (1H, d), 7.70-7.91 (4H, m), 8.25 (1H, s), 8.34 (1H, s wide), 10.40 (1H, wide s).

Example 159 2- [N- (3-Acetylaminobenzoyl) amino] -4 - [(2-diisopropylaminoethyl) aminocarbonyl] -1,3-thiazole

1 H NMR (DMSO-d6) δ: 1.30 (6H, d), 1.33 (6H, d), 2.09 (3H, s), 3.10-3.25 (2H, m), 3.60-3.75 (4H, m), 7.47 (1H, dd), 7.73-7.80 (2H, m), 7.93 (1H, s), 8.42 (1H, t), 9.48 (1H, wide s), 10, 22 (1H, s), 12.72 (1H, s).

Example 160 Hydrochloride 2- [N- (4-nitrobenzoyl) amino] -4 - [(2-diisopropylaminoethyl) aminocarbonyl] -1,3-thiazole

1 H NMR (DMSO-d_ {6}) δ: 1.23-1.41 (12H, m), 3.20 (2H, s), 3.51-3.74 (4H, m), 8.00 (1H, s), 8.26-8.51 (5H, m), 9.53-9.76 (1H, m), 13.17 (1H, s).

Example 161 Dihydrochloride 2- [N- (4-Aminobenzoyl) amino] -4 - [(2-diisopropylaminoethyl) aminocarbonyl] -1,3-thiazole

1 H NMR (DMSO-d_ {6}) δ: 1.25-1.47 (12H, m), 2.89 (2H, s), 3.42-3.75 (4H, m), 4.90-5.98 (4H, m), 6.87-6.94 (2H, m), 7.89 (1H, s), 7.89-7.98 (2H, m), 8.41-8.63 (1H, m), 10.13 (2H, s), 12.43 (1H, s).

Example 162 2- [N- (4-Formylaminobenzoyl) amino] -4 - [(2-diisopropylaminoethyl) aminocarbonyl] -1,3-thiazole

1 H NMR (DMSO-d_ {6}) δ: 0.99 (6H, d), 1.01 (6H, d),  2.15-2.30 (2H, m), 2.54 (2H, wide s), 2.99 (2H, s wide), 7.74 (1H, d), 7.84 (1H, wide s), 7.89 (2H, s), 8.06-8.09 (2H, m), 8.36 (1H, d), 10.54 (1H, s), 12.57 (1H, wide s).

Example 163 2- [N- (4-Acetylaminobenzoyl) amino] -4 - [(2-diisopropylaminoethyl) aminocarbonyl] -1,3-thiazole

1 H NMR (DMSO-d_ {6}) δ: 0.99 (6H, d), 1.03 (6H, d), 2.09 (3H, s), 2.51 (2H, wide s), 2.99 (2H, wide s), 3.15-3.30 (2H, m), 7.73 (1H, d), 7.79 (2H, s), 7.84 (1H, wide s), 8.03-8.07 (2H, m), 10.28 (1H, s), 12.53 (1H, wide s).

Example 164 2- [N- (5-Formylamino-2-hydroxy-4-methoxybenzoyl) amino] -4 - [(2-diisopropylaminoethyl) aminocarbonyl] -1,3-thiazole

1 H NMR (DMSO-d6) δ: 1.08 (6H, d), 1.10 (6H, d), 2.50-2.54 (2H, m), 2.93-3.02 (2H, m), 3.10-3.25 (2H, m), 3.75 (3H, s), 6.28 1H, s), 7.37 (1H, s), 7.98 (1H, s), 8.04 (1H, t), 8.09 (1H, s), 8.17 (1H, s), 8.77 (1H, s), 9.17 (1H, s).

Example 165 2- [N- (5-Amino-2-hydroxy-4-methoxybenzoyl) amino] -4 - [(2-diisopropylaminoethyl) aminocarbonyl] -1,3-thiazole

1 H NMR (DMSO-d_ {6}) δ: 1.20 (12H, d), 3.05-3.25 (2H, m), 3.30-3.50 (2H, m), 3.61 (2H, wide s), 3.70 (3H, s), 4.35 (1H, wide s), 6.66 (1H, s), 7.29 (1H, s), 7.82 (1H, s), 8.66 (1H, t), 9.43 (2H, s wide), 11.75 (1H, wide s).

Example 166 Hydrochloride 2- [N- (5-Acetylamino-2-hydroxy-4-methoxybenzoyl) amino] -4 - [(2-diisopropylaminoethyl) aminocarbonyl] -1,3-thiazole

1 H NMR (DMSO-d6) δ: 1.30 (6H, d), 1.32 (6H, d), 2.06 (3H, s), 3.17 (2H, wide s), 3.50-3.75 (4H, m), 3.87 (3H, s), 6.83 (1H, s), 7.88 (1H, s), 8.42 (1H, s), 8.70 (1H, t), 9.15 (1H, s), 9.22 (1H, wide s), 11.60 (1H, wide s), 12.15 (1H, wide s).

Example 167 2- [N- (4,5-Dimethoxy-2-hydroxybenzoyl) -N-methylamino] -4 - [(2-diisopropylaminoethyl) aminocarbonyl] -1,3-thiazole

1 H NMR (CDCl 3) δ: 1.26-1.62 (12H, m), 3.14-3.22 (2H, m), 3.44-3.69 (4H, m), 3.85 (3H, s), 3.92 (3H, s), 4.04 (3H, s), 6.58-6.62 (1H, m), 6.93 (1H, s), 7.83 (1H, s), 9.29 (1H, s), 11.15-11.41 (1H, m).

Example 168 Maleate 2- [N- (4,5-Dimethoxy-2-hydroxybenzoyl) amino] -4 - [[N- (2-diisopropylaminoethyl) -N-methyl] aminocarbonyl] -1,3-thiazole

1 H NMR (DMSO-d_ {6}) δ: 1.20-1.40 (12H, m), 2.50 (3H, s), 3.26 (2H, wide s), 3.40 (2H, wide s), 3.60-3.75 (4H, m), 3.77 (3H, s), 3.83 (3H, s), 6.62 (2H, s), 7.51 (1H, s), 7.56 (1H, s), 7.71 (1H, wide s), 8.70 (1H, s wide), 12.10 (1H, wide s).

Example 169 Dihydrochloride 2- [N- (2,5-Dihydroxy-4-methoxybenzoyl) amino] -4 - [(2-diisopropylaminoethyl) aminocarbonyl] -1,3-thiazole

IR (KBr) cm -1: 3325, 1665, 1609, 1559

1 H NMR (DMSO-d6) δ: 1.31 (6H, d), 1.34 (6H, d), 3.15 (2H, broad s), 3.50-3.70 (4H, m), 3.77 (3H, s), 6.00 (2H, wide s), 6.77 (1H, s), 7.47 (1H, s), 7.87 (1H, s), 8.71 (1H, wide s), 9.74 (1H, nacho s), 11.50-11.80 (2H, m).

Example 170 2- [N- (2-Methoxy-4-nitrobenzoyl) amino] -4 - [(2-diisopropylaminoethyl) aminocarbonyl] -1,3-thiazole

1 H NMR (CDCl 3) δ: 1.08 (12H, d), 2.63-2.76 (2H, m), 2.98-3.18 (2H, m), 3.39-3.53 (2H, m), 4.25 (3H, s), 7.72 (1H, s), 7.81 (1H, s), 7.94-7.97 (1H, m), 8.01-8.04 (1H, m), 8.50-8.53 (1H, m), 10.95 (1H, s).

Example 171 2- [N- (5-Chloro-4-formylamino-2-methoxybenzoyl) amino] -4 - [(2-diisopropylaminoethyl) aminocarbonyl] -1,3-thiazole

1 H NMR (DMSO-d_ {6}) δ: 1.00-1.20 (12H, m), 2.93 (2H, wide s), 3.20-3.50 (4H, m), 3.97 (3H, s), 7.88 (1H, s), 7.90 (1H, s), 8.25 (1H, s), 8.35 (1H, s width), 8.47 (1H, s), 10.18 (1H, s), 11.62 (1H, s).

Example 172 Hydrochloride 2- [N- (3-nitrobenzoyl) amino] -4 - [(2-dimethylaminoethyl) aminocarbonyl] -1,3-thiazole

1 H NMR (DMSO-d_ {6}) δ: 2.55 (6H, s), 3.24-3.29 (2H, m), 3.56-3.71 (2H, m), 7.87 (1H, s), 8.03 (1H, s), 8.42 (1H, s), 8.47-8.53 (2H, m), 8.94 (1H, dd), 10.30 (2H, s width).

Structural formulas and melting points of the compounds obtained in the Reference Examples 1-6 and in Examples 1-172 it is They show in the following tables.

TABLE 1

       \ vskip1.000000 \ baselineskip
    

8

       \ vskip1.000000 \ baselineskip
    

9

       \ vskip1.000000 \ baselineskip
    

Reference Example 5

       \ vskip1.000000 \ baselineskip
    

10

       \ vskip1.000000 \ baselineskip
    

Melting point: 85.7 to 86.7 ° C

       \ vskip1.000000 \ baselineskip
    

       \ vskip1.000000 \ baselineskip
    

       \ vskip1.000000 \ baselineskip
    

(Table goes to page next)

       \ newpage
    

TABLE 2

eleven

12

TABLE 3

13

TABLE 4

14

fifteen

       \ newpage
    

TABLE 5

16

17

TABLE 6

18

TABLE 7

19

TABLE 8

twenty

TABLE 9

twenty-one

TABLE 10

22

       \ newpage
    

TABLE 11

2. 3

24

       \ newpage
    

TABLE 12

25

26

27

TABLE 13

28

Preparation Example one

Compound of the Example two 20 g Lactose 315 g Cornstarch 125 g Crystalline cellulose 25 g

The ingredients described above were mixed. evenly, followed by the addition of 200 ml of a solution of 7.5% aqueous hydroxypropylcellulose. The resulting mixture is pulverized in granules through a sieve of 0.5 mm in diameter by means of an extrusion granulator. Immediately after that, the resulting granules were rounded by a Marumerizer, followed by drying, whereby a granular agent was obtained.

Preparation Example two

Compound of the Example 24 20 g Lactose 100 g Cornstarch 36 g Crystalline cellulose 30 g Carboxymethylcellulose calcium salt 10 g Magnesium stearate 4 g

The ingredients described above were mixed uniformly. The resulting mixture was compressed in 200 mg tablets by means of a 7.5 mm diameter die in a machine to form single die tablets.

Preparation Example 3

Compound of the Example 30 100 mg Sodium acetate two mg Acetic acid (to adjust the pH to 5.8) c.s. Water distilled c.s. Total 10 ml / vial

In accordance with the above formulation, an injectable was prepared in a manner known per se in the art.

Industrial exploitation capacity

The compound according to the present invention notably intensifies gastrointestinal motility, thereby providing an improvement in digestive dysmotility and at the same time, it manifests high security so that it is useful for the prevention and treatment of various dissimilarities digestive

Claims (14)

1. An aminothiazole derivative represented by the following formula (I): 29 where R 1, R 2 and R 3 are the same or different and each independently represents an atom of hydrogen, a hydroxy group, a lower alkyl group, a group lower alkoxy, a lower alkylcarbonyloxy group, a halogen atom, a nitro group, an amino group, a mono- group or di- (lower alkyl) amino, a mono- or di- (alkyl) group lower) carbonylamino, a formylamino group, a mono- group or di- (lower alkyl) aminoalkylamino, or R1 and R2 they can be coupled together to form a methylenedioxy group; R 4 represents a hydrogen atom or a lower alkyl group; R 5 represents a hydrogen atom, a halogen atom or a lower alkyl group; A represents a group represented by the next formula: 30 where R 6 and R 7 are the same or different and each independently represents a hydrogen atom, a lower alkyl group, a lower alkoxy group, a group hydroxy (lower alkyl), a carboxy group (alkyl lower), a group (lower alkoxy) carbonyl (alkyl lower), an alkoxy (lower) alkyl group, a group mono- or di- (lower alkyl) aminoalkyl, a group phenylalkyl which may be substituted with one or two alkoxy groups lower in the benzene ring, a heterocyclic group that contains saturated or unsaturated nitrogen that may be substituted with a lower alkyl group, or R 6 and R 7, together with the adjacent nitrogen atom, form a heterocyclic group that contains saturated or unsaturated nitrogen that may be substituted with an oxo group (O =) or 1 to 3 lower alkyl groups or hydroxy (lower alkyl), or a group represented by the next formula: 31 where R 8 and R 9 are the same or different and each independently represents an amino group, a group mono- or di- (lower alkyl) amino, a mercapto group or a (lower) alkyl group thio, or R 8 and R 9, together with the adjacent carbon atom, they form a heterocyclic group that contains nitrogen; and B represents an imino group that can be substituted with a lower alkyl group or an oxygen atom; and m represents an integer from 0 to 4; B- (CH2) m -A can form a group piperidinyl, branched alkylamino or phenylamino which may be substituted with a mono- or di- (lower alkyl) amino group, or a piperazinyl, piperidinylamino or piperidinylalkylamino group that it may be substituted with a lower alkyl group, or a salt of the same. 2. A derivative of aminothiazole or a salt thereof according to claim 1, wherein in formula (I), one of R1, R 2 and R 3 represent an alkoxy group C 1 -C 6, nitro or formylamino and the other two are selected from the group consisting of a hydrogen atom, a group hydroxy, a C 1 -C 6 alkyl group, a group C 1 -C 6 alkoxy, a group (C2-C7) alkylcarbonyloxy, a halogen atom, a nitro group, an amino group, a mono- or group di- (C 1 -C 6 alkyl) amino, a group mono- or di- (alkyl C 1 -C 6) carbonylamino, a group formylamino and a mono- or di- (alkyl) group C 1 -C 6) aminoalkyl (C 1 -C 6) amino. 3. An aminothiazole derivative or salt thereof according to claim 1, wherein in formula (I), one of R 1, R 2 and R 3 represents a C 1 alkoxy group -C 6, nitro or formylamino and the other two are selected from the group consisting of a hydrogen atom, a hydroxy group, a C 1 -C 6 alkyl group, a C 1 -alkoxy group - C 6, a (C 2 -C 7) alkylcarbonyloxy group, a halogen atom, a nitro group, an amino group, a mono- or di (C 1 -C 6 alkyl) group }) amino, a mono or di- (C 1 -C 6 alkyl) carbonylamino group, a formylamino group and a mono- or di- (C 1 -C 6 alkyl) amino (C_) alkyl {1} -C6) amino; R 4 represents a hydrogen atom or a C 1 -C 6 alkyl group; R 5 represents a hydrogen atom, a halogen atom or a C 1 -C 6 alkyl group; A represents -N (R 6) R 7 (where R 6 and R 7 have the same meanings defined above); B represents an imino group that may be substituted with a C 1 -C 6 alkyl group; ym

 \ hbox {represents from 2 to
4.} 

4. A derivative of aminothiazole or a salt thereof according to claim 1, wherein in formula (I), one of R1, R 2 and R 3 represent an alkoxy group C 1 -C 6, nitro or formylamino and the other two are selected from the group consisting of a hydrogen atom, a group hydroxy, a C 1 -C 6 alkoxy group and an atom halogen; R 4 and R 5 each represent an atom of hydrogen; B represents an imino group that may be substituted with a C 1 -C 6 alkyl group; m represents from 2 to 4; and A represents -N (R 6) R 7 (in the that R 6 and R 7 have the same defined meanings before). 5. A medicine that comprises as an ingredient effective an aminothiazole derivative (I) as claimed in a any one of claims 1 to 4 or a salt thereof. 6. A medicament according to claim 5, which It is a preventive and therapeutic agent for dismotility digestive 7. A medicament according to claim 5 or 6, which is a preventive or therapeutic agent for discomfort epigastric, nausea, vomiting, heartburn, anorexia, epigastric pain, abdominal flatulence, chronic gastritis, reflux esophagitis and syndrome post-gastrectomy 8. A pharmaceutical composition comprising a aminothiazole derivative (I) or a salt thereof as claimed in any one of claims 1 to 4 and a carrier pharmaceutically acceptable. 9. A composition according to claim 8, which It is a preventive and therapeutic composition for dismotility digestive 10. A composition according to claims 8 or 9, which is a preventive and therapeutic agent for discomfort epigastric, nausea, vomiting, heartburn, anorexia, epigastric pain, abdominal flatulence, chronic gastritis, reflux esophagitis and syndrome post-gastrectomy 11. The use of an aminothiazole derivative (I) or a salt thereof as claimed in any one of the claims 1 to 4 for the manufacture of a medicament. 12. The use according to claim 11, by of which the medicine is a preventive and therapeutic agent for digestive dysmotility 13. The use according to claim 11 or 12 through which the medicine is a preventive agent or Therapeutic for epigastric discomfort, nausea, vomiting, heartburn, anorexia, epigastric pain, flatulence abdominal, chronic gastritis, reflux esophagitis and post-gastrectomy syndrome. 14. A thiazole derivative represented by the following formula (II): 32 where R 1, R 2 and R 3 are the same or different and each independently represents an atom of hydrogen, a hydroxy group, an alkyl group C 1 -C 6, an alkoxy group C_ {1} -C_ {6}, a group (C2-C7) alkylcarbonyloxy, a halogen atom, a nitro group, an amino group, a mono- or group di- (C 1 -C 6 alkyl) amino, a group mono- or di- (alkyl C 1 -C 6) carbonylamino, a group formylamino or a mono- or di- (alkyl) group C 1 -C 6) amino (C 1 -C 6) alkyl, amino, or R 1 and R 2 can be coupled together to form a group methylenedioxy; R 4 represents a hydrogen atom or a group C 1 -C 6 alkyl; R 5 represents an atom of hydrogen, a halogen atom or an alkyl group C 1 -C 6; D represents a hydroxy group or a C 1 -C 6 alkoxy group, or a salt of the same.